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Cystic diseases of the kidney: molecular biology and genetics.

Geneticists have been searching for new genes to explain the inheritance patterns of many genetic diseases, including the cystic diseases of the kidney (CDKs), during the past 3 to 4 decades. With the advent of the 21st century and the completion of the sequencing of the entire human genome in 2003, the identification of genes that are mutated in specific disorders has entered a different era. This very task has become much faster and easier in most cases, although there are exceptions, such as the MCKD1 gene for medullary cystic kidney disease (MCKD) type 1, which remains stubbornly elusive (Figure 1 shows schematically the morbid cystic kidney chromosome map). New genes are being cloned and characterized, which enable researchers to discover, perhaps not unexpectedly and with no surprise, that mutations in many different genes can produce similar phenotypes, with the same general diagnosis and with substantial overlap of symptoms. This significant unprecedented genetic heterogeneity has made molecular diagnostics particularly difficult, as the clinical differential diagnosis does not always help in pointing to the right gene to analyze. (1)

The case for the CDKs is particularly complex, with 9 genes mutated in nephronophthisis, 12 in Bardet-Biedl syndrome, at least 3 in MCKD, and at least 4 in autosomal dominant and recessive polycystic kidney disease (PKD), while the list is destined to expand unpredictably. As the name implies, all these conditions have at least one common morphologic feature, that is, the formation of fluid-filled cysts in the kidney. The cysts are focal entities deriving clonally from dedifferentiated tubular epithelial cells that form a single cell lining with defective polarity. (2) In other cases they essentially represent dilated collecting ducts, such as in the autosomal recessive form of PKD. (3) It is quite interesting that most of the genes mutated in CDKs code for proteins that localize to the primary cilium of the tubular epithelial cells, a fairly recently rediscovered organelle. (4-6) Apparently, there is something that unifies the function of all those diverse proteins in a way that any defect results in this common phenotype with the many faces, as the spectrum of symptoms includes, in addition to the renal involvement, ocular and vascular abnormalities and mental retardation, to name a few.

MECHANISMS OF CYSTOGENESIS

Current knowledge on cyst initiation and development mainly comes from investigations on autosomal dominant polycystic kidney disease (ADPKD), in which cystic pathology is believed to be the result of abnormal cell proliferation and deregulated apoptosis, increased secretion of fluids into the tubular lumen, irregular cell-matrix interactions, and defective cellular polarity. Similar data on other cases of CDKs are usually absent or are inadequate to extract clear conclusions. Nevertheless, in the recent years of ADPKD study, the tubular renal cell cilia have also been implicated in cystogenesis. Given the fact that almost all proteins implicated in CDKs are at least partially localized in the renal cilium, its vital importance is emphasized and the notion that normal cilium structure and function are essential for renal development and maintenance is supported.

[FIGURE 1 OMITTED]

In ADPKD, irregularities affecting the physiologic growth and differentiation in the kidney are attributed to imbalances between cellular apoptosis and proliferation. Activation of oncogenes and growth factor receptors and ligands together with the downregulation of both apoptosis and tumor suppressor proteins influence excess cellular proliferation. Genes associated with proliferation, such as PCNA, c-Myc, and Ki-67, have been found at increased levels in ADPKD cystic epithelial cell cultures and human cystic tissues. (7-10) Sustained apoptosis in the polycystic kidney works synergistically with enhanced proliferation. Thus, normal parenchyma is damaged and consequently substituted by the cystic epithelium and fibrotic tissue. (5) In both ADPKD and autosomal recessive PKD (ARPKD) patients, epidermal growth factor was found to have elevated mitogenic levels and is believed to contribute in the proliferation of cystic cells. Epidermal growth factor receptor heterodimers are abnormally overexpressed and dislocated on the apical (luminal) surface of cyst-lining epithelia resulting in an autocrine response to epidermal growth factor family ligands. (11)

A lot of detailed work has been done with polycystins 1 and 2 (PC-1, PC-2) the gene products of PKD1 and PKD2 that are mutated in ADPKD. The implication of PC-1 in various pathways connected to proliferation, such as G-protein signaling, Wnt signaling, and AP-1, has been recorded. (12-15) It has also been proposed that both polycystins work together to regulate the cell cycle through the Janus kinase-signal transducer and activator of transcription-1 pathway and [p21.sub.waf1] upregulation to induce cell-cycle arrest in [G.sub.0]/[G.sub.1]. (16) Recent work in our laboratory has shown that in a transgenic PKD2 rat model, the mutant PC-2 (PKD2 [1-703]) induces proliferation in primary tubular epithelial cells in a STAT1/p21 independent fashion and is accompanied by alteration in expression of the cyclin dependent kinase inhibitor p57 and the Cdk2. (17)

It has been shown that PC-1 senses nephron and collecting duct urine flow with its long extracellular N-terminal domain while PC-2 responds to this stimulus by generating a [Ca.sup.2+] influx through the cilium and into the renal epithelial cells. (18-20) Influx of [Ca.sup.2+] is boosted by the consequent release of [Ca.sup.2+] in intracellular stores; endoplasmic reticulum (ER) bound PC-2 together with the C-terminus of PC-1 were found to contribute in this procedure, with PC-1 specifically activating the calcineurin/ nuclear factor of activated T-cells signaling process dependable on sustained elevations in intracellular [Ca.sup.2+]. (21) When PC-1/PC-2 expression is limited beyond a given level, a significant decrease in intracellular [Ca.sup.2+] levels is observed, which is believed to cause a cystic phenotype. (22,23) In addition, rapid increase of extracellular [Ca.sup.2+] concentration induces the process of tubular epithelial cell dedifferentiation to commence and cyclic adenosine monophosphate (cAMP) concentration to increase. The mitogen activated protein kinase/extracellular signal-regulated kinases signaling pathway and deregulated cell proliferation are activated by the elevated cAMP levels. (24,25) It has been found that an in vitro increase of [[Ca.sup.2+]] in ADPKD cystic cells is able to inhibit cAMP induced cyst formation, while it suppresses ERK activation. (26) cAMP concentrations are also increased by the vasopressin V2 receptor, a fact that prompted researchers to use vasopressin V2 receptor inhibitors in clinical trials for preventing cyst formation. (27)

Abnormal fluidic secretion observed in ADPKD tubular epithelia is interceded by chloride ion secretion followed by passive water and sodium ion movement. (28,29) Chloride ions are predominantly secreted by the cystic fibrosis transmembrane regulator protein, a chloride channel regulated by cAMP, which in ADPKD cystic cells is dislocated in the apical membrane. (30) Inhibition of cystic fibrosis transmembrane regulator protein expression in both in vivo and in vitro models of PKD decelerated cyst development. (31) Sodium is secreted by the NaK-ATPase, a sodium pump normally found in the basolateral tubular membrane that is also dislocated in the apical surface of ADPKD cystic cells. (32)

Initiation of cyst development in ADPKD has also been tied to changes in tubular basement membrane structure and matrix composition. These changes include defects in collagen and laminin compositions and aberrance of integrin receptors. Laminin [alpha]5 transgenic mice develop polycystic kidneys. (33) Normal PC-1 is localized in focal adhesions and adherens junctions as a complex together with E-cadherin and [alpha]-, [beta]-, and [gamma]-catenins. (34) In ADPKD abnormal focal adhesions and adherens junction complexes occur, while E-cadherin is found to be substituted by N-cadherin. (35) PC-1 has also been found to localize at sites of cell-matrix interaction where it is associated with focal adhesion proteins like integrin, paxillin, vinculin, and the focal adhesion kinase. (36)

More recent work has shown very elegantly that perhaps even more significant than increased proliferation of tubular cells in the course of cyst formation is the deregulated planar cell polarity, thereby upsetting the normal cell division and tubule lengthening, leading instead to cystic dilatation. (37) Fischer et al (38) studied planar cell polarity in the Pkhd1 deficient pck rat and found cells deployed in an irregular manner escaping the tubular axis. Disorientation of cell division intercepts with maintaining the tubular epithelium and leading cell proliferation out of order. Furthermore, the possible implication of the cilium in planar cell polarity has also been addressed. In Kif3a knock-out mice precystic tubules appeared to have irregular planar cell polarity, indicating that primary cilia are required for its maintenance. (37,39) In view of the universal role of the cilium structure and its components, a separate description of it is considered useful (see later).

PRIMARY CILIA

Experimental data show that CDKs can be theoretically unified in the genes implicated in each case (40); proteins encoded by these genes are localized on renal epithelial cells and specifically on the primary cilium itself or the basal body and centrosome, with the only known exception being the gene product of MCKD2, Tamm-Horsfall protein (THP). (41) Various studies have shown that these kidney cyst-associated proteins are involved in processes such as signal transduction, calcium signaling, sensing of the urine flow, cell mitosis, and proliferation. Additionally, they appear to be evolutionarily conserved and most of them cointeract in normal signaling processes. (6,42)

Cilia are plasma membrane bordered finger-shaped projections containing microtubules. (43) Structural and motility characteristics of cilia can classify them into 2 general entities, namely the motile and immotile (primary) cilia. Microtubular axoneme organization in motile cilia follows a 9 + 2 assembly, where 9 doublets of microtubules surround a central pair; this arrangement allows specific movement patterns that can lead fluids toward a single direction in vivo, by the interacting sliding of the different constitutive parts of doublets. (44) Contrastingly, immotile cilia lack the microtubule central pair, thus they cannot be in motion. Interestingly, Kramer-Zucker et al (45) showed that zebrafish pronephric cilia are motile, with a 9 + 2 configuration, while also human fetal kidneys with 9 + 2 bundles of cilia have been observed in kidney tubule lumens. This in itself provided one additional role for cilia, next to sensing urine flow. (46) In the same work, Kramer-Zucker et al also showed movement of 9 + 0 cilia in zebrafish ependymal cells.

Growth of renal cilia is templated from a basal body/ centriole structure anchored just beneath the plasma membrane. The membrane covering the cilium structure maintains its continuity to the rest of the plasma membrane, except that it has different constitution with many molecules that allow the cilium to function as a cell mechanosensor, sensing and interpreting urine flow and composition. (47) Every apical cilium that originates from an epithelial cell extends into the fluid-filled lumen and spans 2 to 4 [micro]m in length. (48) It is possible that the renal cilium acts as a fluid flow sensor through the nephron and collecting duct, an ability emerging from its putative role in maintaining renal architecture. (49)

According to the cilia-cyst theory, altered protein products as a result of mutated genes implicated in CDKs have significant consequences toward the cilium or the basal bodies. (40) Such mutations result in bilateral fluid-filled cyst development that contributes to impaired renal function. Primary cilia play a central role in cystic disease pathogenesis, and multiple organ involvement is attributed to the primary cilia because they constitute the connection between mechanical sensing and osmotic and visual stimuli, while they manage to control the cell-cycle and epithelial cell polarity via cell signaling processes. (40,50) Inversin, the ciliary protein implicated in nephronophthisis type 2, is speculated to provide the connection between mechanosensation of cilia and cyst formation. (20,51) Decrease of [Ca.sup.2+] concentration in epithelial cells enables inversin to stimulate the commencement of the cell cycle. (19) For PKD, cyst formation has been mostly attributed to renal tubular or duct epithelial cell dedifferentiation and improperly elevated levels of cell proliferation. (23,52) Silberberg et al (53) showed that epithelial cell dedifferentiation signifies a regression toward a fetal type of tissue. Additionally, the impaired [Ca.sup.2+] influx, owing to PC-2 inactivation in ADPKD, results in increased secretion of chlorides and fluids in the tubular lumen. (54) The cAMP concentration also increases and acts as a mitogen of cystic epithelium, thus facilitating renal cyst formation. (24,55)

Despite research progress of cystogenesis in ADPKD, it is unclear how defects in primary cilium signaling affect downstream pathways. Bending of cilia by urine flow causes the increase of intracellular calcium probably through PC-2. (54) Furthermore, experimental evidence suggests a link among cilia malfunction and Wnt signaling, planar cell polarity, and cell cycle regulation. (56)

AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE

Autosomal dominant polycystic kidney disease is one of the most common hereditary disorders affecting 1 in 600 to 1 in 1000 individuals. (57) In 85% to 90% of the cases it is coinherited with mutations in the PKD1 gene that maps at the tip of the short arm of chromosome 16 at position 16p13.3. (58,59) The genomic sequence of PKD1 is 52 kb in size and is transcribed into a 14 kb mRNA. It consists of 46 exons with the largest one being exon 15, of approximately 3.2 kb in size. Intron 21 includes the largest polypyrimidine tract yet identified in the human genome. (60,61) It is approximately 2.5 kb long and the coding strand consists of 95% cytosine and thymine. Similar structures have been shown to be prone to mutagenesis due to their capability of forming a triple-strand conformation. It is speculated that the polypyrimidine tract present in the PKD1 gene is responsible, at least partly, for its high mutation rate. (62)

Molecular analysis of the PKD1 gene is particularly cumbersome owing to its unusual length while the sequences containing exons 1 to 33 are duplicated 6 times within the homologous genes, proximally on chromosome 16 (see reference 63 and references therein). The homology of the PKD1 gene sequence to those homologous genes is as high as 90%; therefore, great attention has been given in designing polymerase chain reaction primers in the unique region at the 3' end of the gene or further upstream in regions of lower homology, as a first step for generating long-range polymerase chain reaction products. Analysis is then followed by multiple shorter nested polymerase chain reaction amplification products to cover the entire gene. (64-66)

The PKD2 gene (also referred to as TRPP2) is located on the long arm of chromosome 4 at position 4q22. The genomic sequence covers an area of about 68 kb and is transcribed into a 5.4 kb mRNA. (67) It consists of 15 exons and, unlike PKD1, does not contain a polypyrimidine tract and is considered as a [Ca.sup.2+] -permeable nonselective cation channel. (68,69) Mutations in the PKD2 gene are responsible for 10% to 15% of ADPKD cases, and they confer a lower risk for reaching end-stage renal disease (ESRD) compared with PKD1 mutations. (70) Technically, the analysis of the PKD2 gene is much easier, except for a region in its 5' end encompassing the first exon where the high GC content requires caution for success in amplifying it. (63)

PKD1 gene product, PC-1, is thought to serve as a mechanical sensor that detects flow in the tubule lumen when its projecting extracellular N-terminal domain undergoes conformational changes caused by flow dynamics in the lumen. (71) This N-terminal domain of PC-1 could also be a receptor for an as yet unknown ligand. (72) It is normally localized on primary cilia, in tight and adherens junctions, desmosomes, and focal adhesions. (4)

PKD2 gene product, PC-2, belongs to the transient receptor potential channel family and forms a nonselective calcium ion channel regulated by interactions with PC-1. (73) It can be colocalized with PC-1 on the primary cilium or in the centrosome but can also function singly or by interacting with other potential partners in the ER. (69)

It is worth mentioning the 2-hit hypothesis for cyst formation, according to which a germinal heterozygous mutation is inherited but cell hyperproliferation and cyst formation does not commence unless the second allele is somatically inactivated. (74) This situation is reminiscent to the formation of many tumors when tumor suppressor genes are mutated. In accordance with this, it was shown that there are cases in which the cystic cells carry a germinal heterozygous mutation in the PKD1 allele and a second mutation is acquired that affects one PKD2 allele, thus creating a transheterozygous situation, lending genetic support to the significance of the cooperation between the 2 polycystins. (74-76) In addition, in vitro experiments showed indeed that the 2 polycystins interact with each other through their C-terminal intracellular domains with coiled-coil structure. (77)

A major challenge in the diagnosis of ADPKD based on the molecular analysis of these genes, and especially the PKD1 gene, is associated with the frequency of sequence variants that cannot be interpreted easily as being pathogenic or not. According to 2 recent publications in which the authors attempted an in-depth analysis of both PKD genes, only two thirds, at the most, can be definitively classified as pathogenic, whereas additional variants can be classified as likely pathogenic after further evaluation or as unclassified variants. In the PKD1 gene every person is proved to have more than 10 polymorphic variants, making diagnosis difficult. If no additional family members are available for segregation and linkage analysis it is impossible to classify such polymorphic variants as related to the disease inheritance, and even then one cannot exclude linkage disequilibrium to the real mutation. (65,66,78) Therefore, caution must be exercised when offering molecular analysis and genetic counseling to the probands or family members. Garcia-Gonzalez et al (65) made use of the effect some mutations near the extracellular protein domain encompassing the G-protein-coupled receptor proteolytic site sequence might have on the cleavage of PC-1 at this site to evaluate functionally the putatively pathogenic role of variants. This, however, is not a test that can easily be adopted routinely. Another issue is the finding of more than one potentially pathogenic variants in a patient, in cis, thus raising the possibility of synergistic effects for decreased or otherwise aberrant expression of the gene. (65,66,78)

Interfamilial clinical heterogeneity has also been recorded in ADPKD kindreds and a significant part of this variability can be explained by locus heterogeneity. A sound explanation of this is attributed to the inheritance of mutations in either of the 2 genes, PKD1 or PKD2, as it is well-known that PKD2 mutation carriers follow a milder course, with later age at onset and lower risk for reaching ESRD. (79,80) However, an equally high degree of intrafamilial heterogeneity, in which patients carry the same germinal mutation, can be attributed to other factors, genetic or otherwise. There is clearly a gender effect, with women reaching ESRD at later age (76.0 years; 95% confidence interval, 73.8-78.1 versus 68.1 years; 95% confidence interval, 66.0-70.2). (81) It has been shown that the site of the PKD2 mutation does not play a role, while surprisingly patients with splice site mutations appeared to have milder renal symptoms compared with patients with other types of mutations. (81) Furthermore, the group of Peter Harris showed that mutations in the 5' half of the PKD1 gene confer more severe disease compared with mutations in the 3' half. (82) Fain et al (83) demonstrated that up to 18% to 59% of the phenotypic expression of PKD1 mutations can be attributed to genetic modifiers. A similar study by Paterson et al (84) showed that in patients prior to reaching ESRD, the heritability of phenotypic variation was 42%, whereas for patients with ESRD it was estimated to 78%. Several articles investigated the putative role of polymorphisms in the endothelial nitric oxide synthase gene (ENOS) as a modifier in ADPKD with mixed results. (85,86) Finally, a meta-analysis for the role of the angiotensin converting enzyme insertion/deletion polymorphism failed to confirm any association. (87)

In view of the advent of new knowledge relating to such common monogenic disorders as ADPKD and the application of several therapies already in phase III clinical trials, the early molecular diagnosis of people at risk obtains new practical meaning. One hopes that, in addition to the diagnosis for psychological reasons or for modifying the lifestyle to preserve kidney function longer, it will be of utmost importance in instituting timely therapy aimed at preventing cyst formation all together.

In our set up in Cyprus, where we usually have easy access to large families, we routinely perform DNA linkage analysis for establishing phase and indirect molecular diagnosis. It is indeed necessary to contact clinically affected and healthy relatives to perform this indirect kind of genetic testing, with the use of multiple flanking polymorphic markers. This allows the observation of the concordance of inheritance of the disease phenotype with entire molecular haplotypes that represent entire chromosomal regions, encompassing our gene of interest. Our population is usually very responsive to such approach, thereby facilitating the diagnosis without having to sequence both genes, PKD1 and PKD2, with the pitfalls of identifying several unclassified variants, in addition to the high cost. Due to the genetic heterogeneity, and although the PKD1 mutations are much more frequent than PKD2 mutations, nevertheless linkage analysis with at least 4 flanking markers is always performed for reaching trusty conclusions, followed by proper genetic counseling. (88,89)

AUTOSOMAL RECESSIVE POLYCYSTIC KIDNEY DISEASE

Autosomal recessive polycystic kidney disease is a cystic variant of PKD emerging from mutations in the PKHD1 gene. (90) Although a rare disorder with 1 affected of 20 000 newborns, ARPKD is a severe congenital disorder manifesting with large cystic kidneys, congenital hepatic fibrosis, and systemic hypertension that manifests in the early years of life with almost half of affected newborns dying soon after birth due to pulmonary hypoplasia. (50,91,92) Ultrasound imaging presents enlarged, bilaterally echogenic kidneys and multiple cysts in the renal medulla, while liver depiction includes hepatomegaly, biliary ectasia, and increased tissue echogenicity. (93)

Phenotypic variability in ARPKD patients can be explained by the nature of PKHD1 gene itself; alternative splicing of its 86 exons assembles a variable number of transcripts with the longest being fibrocystin/polyductin. (92) Therefore, mutation localization is a critical event that determines pathologic characteristics for each case. Truncating mutations are usually the reason for a more severe disease, with most patients dying during the perinatal period. (94,95)

Fibrocystin/polyductin is predominantly expressed in the kidney and in lesser amounts in the liver and pancreas and is significantly homologous to a protein superfamily involved in regulating proliferation and adhesion or repulsion properties of cells. (96) In renal epithelial cells, at least part of fibrocystin/polyductin is localized to the renal epithelial primary cilium and the centrosome. (96,97) Interaction of fibrocystin/polyductin with polycystins has been proposed and it is postulated that these proteins belong to a network, namely the PKD transcriptional network. (98) In mice bearing a homozygous deletion in Pkhd1 and a single mutation in Pkd1, the ARPKD-PKD mosaic phenotype was more severe than if any 1 of the 2 genes was mutated separately, while 2 transallelic mutations in Pkd1 resulted in embryonic lethality. (99)

NEPHRONOPHTHISIS

The nephronophthisis group of disorders currently comprises 9 different types that correspond to 9 different genes. They are inherited in an autosomal recessive manner and mainly affect the tubular kidney histology, while they encompass a variable range of extrarenal manifestations depending on the responsible gene (Table). (100) The localization to the cilium of nephronophthisis proteins that are differentially expressed in various tissues is thought to constitute the primary connection among different disease types, their histologic and ultrasonographic picture, and the tissue of supplemental symptoms. (40) Further, age of onset classifies this group; there are 3 distinct age groups: the infantile, juvenile, and adolescent. (101-103) The juvenile form is most frequent and has a discrete histologic representation of characteristics that include the thickening of tubular basement membrane followed by tubular atrophy, together with diffuse interstitial fibrosis. End-stage renal disease has been reported at the age of 13 years. (102) Adolescent nephronophthisis shares a similar pathologic picture with the juvenile form but has a later ESRD onset at 19 years. (103)

Prediagnosis for juvenile nephronophthisis, at a median age of 6 years, is signified by early polyuria and nighttime polydipsia, both related to salt wasting, which results in hyponatremia and hypovolemia. (104) A decrease in urinary concentrating ability by the kidney and secondary enuresis are also observed in most cases. (105) Later symptoms include growth delay, while proteinuria and hematuria are minimal or absent. (106,107) Diagnosis could be impeded by the absence of hypertension, urinary tract infections, or edema, thus increasing the risk of a sudden death from fluid and electrolyte imbalance. (40) Cysts are usually small and located at the corticomedullary junction, while ultrasonographic imaging shows normal or smaller sized kidneys, loss of corticomedullary differentiation, and renal parenchymal hyperechogenicity. (106) Loss of normal tissue rather than abnormal cell proliferation is responsible for cyst development. All of these lead to chronic dehydration, and finally renal insufficiency is followed by anorexia and anemia, together with nausea, weakness, and metabolic acidosis. (108,109)

Nephrocystins (NPHP) are proteins localized at adherens junctions and focal adhesions. (106) Most of them are responsible for the juvenile type, while NPHP3 is found in the adolescent. NPHP1 can interact with other nephronophthisis proteins through its src homology 3 and coiled-coil domains. (110) It has been characterized as a docking protein creating networks with p130Cas, focal adhesion kinase 2, tensin, and filamins A and B to establish cell polarity and regulate signaling processes between cells and among the cells and the matrix. (42) Homozygous deletions of an approximately 200 kb region in NPHP1 , account for 20% to 40% of cases. Compound heterozygosities are usually the result of a heterozygous deletion and a point mutation in the other of the 2 alleles. (106) Characterized as cerebello-oculo-renal syndromes, different types of Senior-Locken syndrome (SLSN), Joubert syndrome (JBTS), Meckel-Gruber syndrome, and Bardet-Biedl syndrome have all been associated with and are allelic with various nephronophthisis loci (Table). (111) Leber congenital amaurosis, a severe retinal dystrophy progressing to visual impairment or blindness, is the main clinical symptom of SLSN, which was described to be allelic with NPHP3 in a German consanguineous family. (112,113) NPHP4 interacts with NPHP1, and loss-of-function protein truncating mutations were found in SLSN type 4 patients with retinitis pigmentosa (RP). (114) Mutations in NPHP5 present RP together with renal tubular abnormalities. The same gene is implicated in SLSN type 5 with X-linked RP, emerging from interactions between the 2 IQ domains of NPHP5 with the GTPase regulator of RP; these proteins colocalize both at photoreceptor connecting cilia and renal primary cilia in epithelial cells. (115) Retinitis pigmentosa and cerebellar defects are attributed to NPHP6 mutations that also can cause JBTS type 5. (116,117) Additionally, mutations in NPHP6 cause most cases of Leber congenital amaurosis. (118) NPHP6 is expressed in centrosomes and the mitotic spindle regulates transcription factor activity, such as the ATF4/CREB2 that has been implicated in cAMP-dependent renal cyst phenotype. (116) GLIS2 or NPHP7 is thought to be essential for maintaining normal renal function and is a Kruppel-like ZNF transcription factor protein; Glis2-ablated mice models develop a nephronophthisis distinctive histologic picture progressing to renal failure, perhaps due to an overexpression triggering effect toward genes implicated in proinflammatory or profibrotic processes. (119,120) Both JBTS type 7 and Meckel-Gruber syndrome type 5 are ascribed to truncating mutations on NPHP8/RPGRIP1L gene, located at 6q12.2 and primarily localized to the base and axoneme of cilia in the kidney, brain, and retina. (121) These mutations are thought to interrupt the protein's normal interaction with NPHP4, especially if they occur at its central protein kinase C conserved region; NPHP4 is then failing to transfer RPGIP1L from the cytoplasm to the centrosome. (122) The most recently described type 9 of the nephronophthisis group is due to missense mutations at NEK8/NPHP9 gene, which is considered as the link between nephronophthisis and PKD. (123) In Nek8 and Pkd1 mutated jck murine models, coexistence of mutations in both genes was found to be directly related to an increase in emerging cysts and this is suggestive of a common mechanism leading to renal cystic pathogenesis. (124) Although the role of NEK8 in cystogenesis was established earlier, when the G448V NEK8 mutation bearing jck mouse model was developed, Otto and colleagues (125) in 2008 found missense mutations in patients previously diagnosed with nephronophthisis.

The infantile form of nephronophthisis is usually diagnosed during the first few years after birth. Slightly different than juvenile and adolescent forms, NPHP2 related nephronophthisis is more aggressive and has a microscopic histologic picture that resembles PKD, with cortical cysts and increased kidney size, cystic dilatation of collecting ducts, and hypertension. (51) Tubular damage is absent. The gene responsible for this type is NPHP2 coding for inversin, a protein that is known to regulate the switch between the canonical and the noncanonical pathway of Wnt signaling. In mice models, it was found responsible for the left-right axis orientation of fetal tissues; thus, extrarenal manifestations are associated with malfunctions in left-right asymmetry, like situs inversus as found recently in an adolescent. (51,126)

Due to the great genetic heterogeneity with 9 genes involved thus far, molecular investigation of individual patients with nephronophthisis becomes very difficult, time consuming, and expensive. The family history or the detailed clinical picture and the spectrum of symptoms of the patient may assist in excluding certain candidate genes. Otto et al (127) used a combined approach in which mutation analysis was performed by heteroduplex CEL I endonuclease digests of all exon-polymerase chain reaction products of the respective NPHP genes. Any cleavage products were taken as evidence for mutation or polymorphism presence and were sequenced. In many cases the researchers started with homozygosity mapping using 3 markers of high heterozygosity index, an approach that revealed that many patients are homozygous for certain mutations, even though parent consanguinity was not always reported or documented. Interestingly, approximately 25% of patients are homozygous for the large deletion in the NPHP1 gene, while a smaller fraction are compound heterozygous. The use of CEL I endonuclease for heteroduplex cleavage, after addition of sample from healthy controls, proved very simple, effective, and inexpensive. (127)

Patients younger than 5 years with ESRD should mainly be screened for mutations in the NPHP2 gene (infantile type), although an overlap with mutations in the NPHP3 gene is possible, as it was described in 2 children with NPHP3 mutations and ESRD below this age cut-off. (127) Based on clinical presentation, Salomon et al (106) suggest an algorithm according to which patients older than 5 years with ESRD should be first tested for NPHP1 and depending on the nature of extrarenal symptoms be tested for NPHP5 (severe RP), for NPHP6 (severe RP and cerebellar ataxia), or for NPHP8 (cerebellar ataxia without severe RP). Mutations in the NPHP3, NPHP4, NPHP7, and NPHP9 are very rare and not routinely screened. Based on the large number of patients, perhaps close to two thirds, without mutations in the presently known genes, it is anticipated that many more genes will be identified to be responsible for nephronophthisis phenotype.

[FIGURE 2 OMITTED]

MEDULLARY CYSTIC KIDNEY DISEASE

Medullary cystic kidney disease is an autosomal dominant condition with age-dependent penetrance than can lead to ESRD at any point from the third to the seventh decade of life. Two clinically indistinguishable types of MCKD, sharing a similar histologic picture with nephronophthisis, have been characterized to this point. Extrarenal symptoms are absent, except for hyperuricemia, which in some cases is manifested as gout. Collaborative work in our laboratory identified a few large Greek-Cypriot families in Cyprus, sharing the same haplotype, and mapped the MCKD1 gene on chromosome 1q21-q23. (128-130) Since then, we and others have identified more families of Greek, British, German, American, or Finish descent linked to this locus; however, the gene has not been cloned yet, despite extensive analysis and DNA sequencing of tens of genes (131-137) (and C.D. et al, unpublished results, 2009) (Figure 2). Nevertheless, the region has been studied in depth and has been significantly but not sufficiently fine mapped through the years, both by the characterization of useful recombinants and by identifying apparently nonrelated families that shared extended haplotypes. Locus heterogeneity was confirmed by mapping and cloning the MCKD2 gene, encoding uromodulin (or THP),138 while lack of linkage of families to either 1 of the 2 loci implies the existence of yet another locus. (139,140)

MCKD2-linked families have an earlier age of onset of ESRD than MCKD1 -linked families. Interestingly, familial juvenile hyperuricemic nephropathy (FJHN) and glomerulocystic kidney disease, (141,142) both being rare but distinct disorders, are allelic to MCKD2 (unilocus mutational and phenotypic diversity). In FJHN, Bowman space is dilated forming cysts and glomerular tuft collapses. Predominant features of autosomal dominant FJHN resemble MCKD2, with hyperuricemia-associated gouty arthritis and early progression to renal failure. (143) Reduced fractional excretion of uric acid and impaired urine concentration ability of the kidney are the major clinical manifestations of glomerulocystic kidney disease, in which kidneys either appear hypoplastic or have a normal size. (144)

However, the actual pathogenic features of uromodulin mutations are still unknown, as is their connection to the cystic phenotype. The clinical picture in these diseases denotes a diffuse intracellular uromodulin aggregation, followed by age- and sex-dependent decreased excretion in the urine. (145) Uromodulin is the most abundant urinary protein and has an unclear function in renal tissue. It is mainly expressed at the luminal side of renal epithelial cells at the thick ascending limb of Henle loop and at the beginnings of distal convoluted tubules. (146) In its natural form, uromodulin is a polymeric protein composed of many 85-kDa monomeric subunits that are intertwined in a helical structure. (147) The zona pellucida domain of the protein helps its polymerization, while the central part of the protein constitutes 3 calcium-binding epidermal growth factor-like domains and a signal peptide. (148) Further, it is characterized by its glycosyl phosphatidylinositol anchor similar domain formed at the C-terminus by a series of hydrophobic amino acids, which act as a signal for ER transpeptidase. (149,150) In normal tissues, the protein is specifically cleaved at the large ectodomain of its glycosyl phosphatidylinositol-anchored domain by the ER transpeptidase and in this manner it is released in the urine. (150)

Early findings have proposed a protective activity of uromodulin against urinary tract infections. Usually caused by intestinal microbes and influenced by the lack of physical barriers and a balanced inflammatory response against them in the urinary tract, recurrent infections can lead to kidney damage and in some cases death. (151) In Umod knock-out mice, bladder susceptibility to colonization by Escherichia coli was observed, because THP is thought to act as a means of innate defense by preventing binding of Ecolito the urothelial surface; wildtype purified THP is capable of binding to type 1-fimbriated Ecolito prevent them from binding to uroplakins. (152-154) In contrast, in a case in which transgenic mice harbor the mutant human UMOD gene (mutation C148W), which was controlled by the mouse Umod promoter, protein accumulation was observed in subjects, but its excretion in the urine was not diminished and creatinine clearance remained normal. (145) This is suggestive of a complex mechanism in which THP actually interacts with several other agents, which are possibly species specific. Additionally, THP has been associated with renal immune responses, salt and water transport, urate metabolism, and inhibition of renal stone formation and has a protective action against ischemic injury in the kidney by decreasing inflammation. (155-157)

Countereffects caused from uromodulin participation in these responses is the abnormally elevated levels of antibodies raised against irregular protein deposition in the tubular interstitium. (158) These antibodies are responsible for most of the damage caused during scarring processes following inflammation in many different cases of urinary tract infection involving various parts of the kidney and enhancing the possibility of renal insufficiency. (151,156) Takiue et al (159) developed transgenic mice carrying the human mutant UMOD gene and observed accumulation of the mouse intrinsic THP, influenced by the mutant human form. Consequently, they proposed a mechanism for protein accumulation in the thick ascending limb: Lower molecular weight intrinsic mouse THP is accumulated by the mutant THP in the plasma membrane, where the gradually increasing concentration of the protein depletes its urinary excretion; thus, export from the ER to the plasma membrane is constricted and THP accumulates in ER to initially induce apoptosis followed by progressive renal damage. Therefore, 1 mutant allele in these autosomal dominant disorders can potentially enhance protein accumulation and consequently numbers of antibodies raised against THP. It is postulated that exons 4 and 5 of the human UMOD gene, coding for the calcium-binding epidermal growth factor-like domain, are of high importance for the protein's properties because frequent mutations reported in these exons are associated with MCKD2 and FJHN. (41,146,148) UMOD is the only known cystic kidney disease-related gene that is not expressed in the cilium of tubular epithelial cells. Spurious single nucleotide substitutions rather than frameshift or nonsense mutations in UMOD disrupt the tertiary structure of the protein, thus enhancing accumulation of uromodulin in the ER of thick ascending limb cells. (160) Physiologic properties of THP such as protein-binding, mononuclear cell proliferating ability, and its neutrophil phagocytosis-enhancing behavior depend directly on the protein core, which is important to remain intact rather than carbohydrate side chains. (161)

ALLELIC HETEROGENEITY AND MUTATION COMPLEXITY IN CDKs

Cystic diseases of the kidney present a great phenotypic variation. Thus, it is usually difficult and risky to classify a disease entity both molecularly and genetically when different mutations on a given gene are responsible for a diverse phenotype. Molecular research through the years has marked off the boundaries dividing different disease entities, but in some cases the observed unilocus mutational and phenotypic diversity blurs the picture. Further complexity arises when considering the genetic characteristics of the genes involved in these diseases. Due to their ciliary or centrosomal localization, CDKs-related genes should work synergistically to maintain normal function of kidneys, but the question remains on how all these clinical entities connect. Are they different sides of the same multifaceted coin or randomly adjacent malfunctions?

The MCKD-FJHN-glomerulocystic kidney disease complex of diseases is a great example of allelic convergence, or unilocus mutational and phenotypic diversity, in the sense that mutations in a single gene present with varying clinical diagnosis. A triad of diseases has been fully linked to UMOD gene mutations, namely MCKD type 2, FJHN, and glomerulocystic kidney disease. Although phenotypically different, allelism is attributed to the disability of uromodulin excretion in affected tubules leading to hyperuricemia. (142) Noteworthy, even identical mutations have been associated with more than one of the former disorders. (162-164) Wolf et al (163) when investigating 11 different families found mutation C744G to segregate in both FJHN and MCKD2 unrelated patients and this is suggestive of a founder effect being spread around Europe.

When observing the nephronophthisis group of diseases, as more genes are identified the spectrum of symptoms expands. As mentioned previously, syndromes such as JBTS, SLSN (Leber congenital amaurosis), and Meckel-Gruber syndrome are encoded by genes whose protein products colocalize with most nephronophthisis responsible genes. Digenic or oligogenic inheritance has been reported, as some patients carry 2 or even 3 mutations in more than one related genes. A similar situation has been described for the Bardet-Biedl syndrome. This signifies that these genes have similar roles or related functions. For example, NPHP6 (CEP290) mutations, in addition to juvenile nephronophthisis, usually trigger both JBTS and Meckel-Gruber syndrome. Recently, Tory and colleagues (165) proposed epistatic effects against NPHP1 mutations from mutated NPHP6 and AHI1 in patients recorded with JBTS. Mutational analysis in 250 patients with type 4 nephronophthisis, SLSN, and Cogan syndrome identified only a limited number of mutations in homozygosity; most sequence variants were found in only 1 of the 2 alleles of NPHP4. (166) It is still unclear which mutations account for every nephronophthisis-related syndrome variant; thus, evaluation of mutation frequencies among groups of patients with a distinct diagnosis and marking of the genetic overlap between them can assist in further delineation of the phenotypic and genetic heterogeneity that makes the situation so complex.

In addition to nephronophthisis, in ADPKD and ARPKD part of the complexity in molecular diagnosis lies with the plethora of mutations inherited by the patients who belong to different families. Also, as mentioned earlier, it is often difficult to evaluate the role of genetic changes observed. It is remarkable that more than 35% of mutations observed in PKHD1 are not recurrent and segregate within specific families. (91) In the same way, recurrent mutations in all nephronophthisis genes are not observed frequently, while in most cases subjects with a distinct phenotype do not carry mutations in the respective genes and genetic linkage to known loci is excluded. Therefore, it is more than certain that many more genes are to be found and perhaps we are just touching the surface of what is going to be one of the most complicated chapters in genetics.

CONCLUDING REMARKS

The practice of clinical nephrology has changed during the past decades owing to significant progress in the molecular genetics of inherited kidney diseases as well as to developments in molecular technologies. The identification of more and more genes has contributed to better classification of genetic conditions but has not always improved therapeutic implications and has not given us enough clues that we are approaching the completion of the chromosomal map of the CDK. At the same time, genetic and allelic heterogeneity, in the presence of unilocus mutational and phenotypic diversity, is making things complicated while it is providing clues for implicating epistatic effects and modifier gene function in interpreting the complex picture we are faced with. Several experts have said that advances in molecular tools and biotechnology for easy molecular diagnostics will certainly be a major contribution to easier differential diagnosis and correct treatment. One hopes that every nephrology clinic will have access to a competent molecular genetics laboratory for consultation and provision of services, while a good clinical history is of great help in guiding the molecular testing. (1)

It is still true though, that for familial conditions, a good detailed pedigree next to a good clinical history goes a long way in excluding related conditions and concentrating on others. The detection of pathogenic mutations with high fidelity and sensitivity using advanced next generation resequencing technology will many times prove to be the gold standard in guiding the clinician, although the oligogenic inheritance and the modifier gene functions, including the recent involvement of microRNA roles, blurs the picture.

On the one hand it is disappointing that Hildebrandt et al (6) in a recent review on nephronophthisis revealed that an impressive 70% of cases diagnosed with nephronophthisis remain to be associated with a genetic cause, as none of the 9 nephronophthisis types we know thus far are responsible. In fact, nephronophthisis type 1 is the most usual type of nephronophthisis with only 21% of cases to be associated, while the rest have frequencies of less than 3%. On the other hand it is encouraging that organized collections of clinical material and biobanking activities funded all over Europe, the United States, and Asia will provide the resources for covering this gap of genetic information on yet many CDKs as well as other categories of genetic kidney conditions, either of mendelian or more complex inheritance. All this, one hopes, will promote translational medicine research to the great benefit of the patient of the 21st century.

We thank K. Felekkis, PhD, for his assistance and critical review of the manuscript. This work was mainly funded through a grant by the Cyprus Research Promotion Foundation, YrEIA/ 0104/04, and partly by the Cyprus Ministry of Health and the George & Maria Tyrimos endowment through a scholarship by the Pancyprian Gymnasium (Dr Deltas).

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Constantinos Deltas, PhD; Gregory Papagregoriou, MRes

Accepted for publication April 7, 2009.

From the Department of Biological Sciences, Laboratory of Molecular and Medical Genetics, University of Cyprus, Nicosia, Cyprus.

The authors have no relevant financial interest in the products or companies described in this article.

Presented in part at the 4th Annual Renal Pathology Society/Kidney and Urology Foundation of America satellite meeting held in association with the 21st European Congress of Pathology, Istanbul, Turkey, September 13, 2007.

Reprints: Constantinos Deltas, PhD, Department of Biological Sciences, Laboratory of Molecular and Medical Genetics, University of Cyprus, Kallipoleos 75, 1678 Nicosia, Cyprus (e-mail: Deltas@ucy.ac.cy).
Genes and Proteins Implicated in Cystic Diseases of the Kidney

     Disease          Gene              Protein

Polycystic Kidney Disease

Autosomal domi-     PKD1        Polycystin-1
  nant PKD1         16p13.3     460 kDa
Autosomal domi-     PKD2        Polycystin-2
  nant PKD2         4q21        110 kDa
Autosomal           PKHD1       Polyductin/fibrocystin
  recessive         6p12.2      447 kDa
  PKD

           Autosomal Recessive Nephronophthisis

NPHP 1/JBTS 4/      NPHP1       Nephrocystin-1
  SLSN 1            2q13        83.3 kDa
NPHP 3/SLSN 3       NPHP3       Nephrocystin-3
                    3q22.1      150.8 kDa
NPHP 4/SLSN 4       NPHP4       Nephroretinin
                    1p36        157.8 kDa
NPHP 5/SLSN 5       IQCB1       Nephrocystin-5
                    3q21.1      68.9 kDa
NPHP 6/JBTS 5/      CEP290      Centrosomal protein
  SLSN 6/MKS 4      12q21.3     290 kDa
NPHP 7              GLIS2       Nephrocystin-7 55.7 kDa
                    16p13.3
NPHP 8/JBTS 7/      RPGRIP1L1   Retinitis pigmentosa
  MKS 5             16q12.2       GTPase regulator
                                  interacting protein
                                1-like 1
                                130.5 kDa
NPHP 9              NEK8        NIMA-related ki-
                    17q11.1       nase 8
NPHP 2              INVS        Inversin
                    9q31        118 kDa

Additional Autosomal Recessive Syndromes Associated With
                     Nephronophthisis

JBTS 1              JBTS1       Unknown
                    9q34.3
JBTS 2              JBTS2       Unknown
                    11p12-
                      13.3
JBTS 3              AHI1        Jouberin/Abelson
                    6q23.3        helper integration
                                  site
                                137.1 kDa
JBTS 6/MKS 3        TMEM67      Transmembrane pro-
                    8q21.13-      tein 67
                      q22.1     110 kDa
MKS 1               MKS1        FABB proteome-like
                    17q22         protein
BBS 1               BBS1        BBS2-like protein 2
                    11q13       65.1 kDa
BBS 2               BBS2        BBS protein 2
                    16q21       79.9 kDa
BBS 3               ARL6        ADP-ribosylation fac-
                    3q21.1        tor-like 6
BBS 4               BBS4        21.1 kDa
                    15q22.3-    BBS protein 4
                      q23       58.3 kDa
BBS 5               BBS5        BBS protein 5
                    2q31.1      38.7 kDa
BBS 6               MKKS        McKusick-Kaufmann
                    20p12         syndrome protein
BBS 7               BBS7        62.3 kDa
                    4q27        BBS2-like protein 1
BBS 8               TTC8        78.5 kDa
                    14q31.3     Tetratricopeptide re-
                                  peat domain pro-
                                  tein 8
BBS 9               PTHB1       Parathyroid hormone-
                    7p14          responsive B1 pro-
                                  tein
                                99.3 kDa
BBS 10              C12orf58    Chromosome 12
                    12q21.2       open reading frame
                                  58
                                80.8 kDa
BBS 11              TRIM32      Transactivator of tran-
                    9q33.1        scription-interac-
                                  tive protein
                                71.9 kDa
BBS 12              C4orf24     Chromosome 4 open
                    4q26-27       reading frame 24
                                79.1 kDa

Autosomal Dominant Medullary Cystic Kidney Disease/Familial Juvenile
      Hyperuricemic Nephropathy/Glomerulocystic Kidney Disease

ADMCKD1             Unknown     Unknown
                    1q21-q23
ADMCKD2/FJHN/       UMOD        Uromodulin/Tamm-
GCKD                16p13.11      Horsfall protein

           Other Diseases With Cystic Renal Phenotype

X-linked            OFD1        Chromosome X open
  orofaciodigital   Xp22.2-       reading frame 5
  syndrome 1          p22.3     116 kDa
Autosomal           ALMS1       Alstrom syndrome 1
  recessive         2p13
  Alstrom
  syndrome 1

                          Localization in
     Disease          Renal Epithelial Cells

              Polycystic Kidney Disease

Autosomal domi-     Primary cilia
  nant PKD1         Focal adhesions
Autosomal domi-     Adherens junctions
  nant PKD2
Autosomal           Primary cilia
  recessive         Apical membrane
  PKD

        Autosomal Recessive Nephronophthisis

NPHP 1/JBTS 4/      Primary cilia ([beta]-tubu-
  SLSN 1              lin)
                    Focal adhesions
                    Adherens junctions
                    Centrosome
NPHP 3/SLSN 3       Primary cilia
NPHP 4/SLSN 4       Primary cilia axoneme
                    Basal bodies
NPHP 5/SLSN 5       Primary cilia
NPHP 6/JBTS 5/      Centrosome of divid-
  SLSN 6/MKS 4        ing cells
NPHP 7              Primary cilia
NPHP 8/JBTS 7/      Ciliary axoneme
  MKS 5             Basal bodies
                    Centrosome
                    Cytoplasm
NPHP 9              Primary cilia
NPHP 2              Primary cilia

Additional Autosomal Recessive Syndromes Associated With
                     Nephronophthisis

JBTS 1              Unknown
JBTS 2              Unknown
JBTS 3              Nuclear
JBTS 6/MKS 3        Primary cilia
                    Cytoplasm
                    Endoplasmic reticulum
MKS 1               Cytoplasm
                    Cytoskeleton
                    Centrosome
                    Basal bodies
BBS 1               Centrosome
BBS 2               Centrosome
                    Primary cilia
BBS 3
BBS 4
BBS 5               Centrosome
BBS 6               Centrosome
                    Primary cilia
BBS 7
BBS 8
BBS 9               Unknown
BBS 10              Unknown
BBS 11              Cytoskeleton
BBS 12              Pericentriolar region of
                      basal bodies and
                      centrosomes
                    Cytoskeleton
                    Microtubules

Autosomal Dominant Medullary Cystic Kidney Disease/Familial Juvenile
    Hyperuricemic Nephropathy/ Glomerulocystic Kidney Disease

ADMCKD1             Unknown
ADMCKD2/FJHN/       Cytoplasm
GCKD                Apical vesicles of
                      thick ascending
                      limb of Henle loop

            Other Diseases With Cystic Renal Phenotype

X-linked            Primary cilia
  orofaciodigital   Basal body
  syndrome 1        Cytoplasm
                    Cytoskeleton
                    Microtubules
                    Centrosome
Autosomal           Cytoplasm
  recessive         Cytoskeleton
  Alstrom           Microtubules
  syndrome 1        Centrosome
                    Centriole

     Disease                Renal Symptoms

             Polycystic Kidney Disease

Autosomal domi-     Increased kidney size
  nant PKD1         Echogenic kidneys
Autosomal domi-     Cortical cysts
  nant PKD2         Cystic dilatation
                    Severe hypertension
Autosomal           Same as autosomal domi-
  recessive           nant PKD
  PKD               Kidney collecting-duct
                    ectasia

       Autosomal Recessive Nephronophthisis

NPHP 1/JBTS 4/      Tubular BM thickening
  SLSN 1            Tubular atrophy
                    Diffuse interstitial fibrosis
                    Small corticomedullary
                      cysts
NPHP 3/SLSN 3       Increased or normal kidney
                      size
NPHP 4/SLSN 4       Salt wasting leading to hy-
                    ponatremia and hypovo-
NPHP 5/SLSN 5         lemia
                    Polyuria and polydipsia
                    Anemia, anorexia, nausea,
NPHP 6/JBTS 5/        metabolic acidosis,
  SLSN 6/MKS 4        weakness
                    ESRD: juvenile form at 13
                      years, adolescent form at
                      19 years
NPHP 7
NPHP 8/JBTS 7/
  MKS 5
NPHP 9
NPHP 2              Increased kidney size
                    Cortical cysts
                    Cystic dilatation
                    Severe hypertension

Additional Autosomal Recessive Syndromes Associated With
                     Nephronophthisis

JBTS 1              Similar to NPHP when
                      reported
JBTS 2
JBTS 3
JBTS 6/MKS 3        Bilateral renal cystic dys-
                      plasia
MKS 1               Enlarged multicystic
                      kidneys
BBS 1
BBS 2               Nephronophthisis-similar
                    Urinary tract malformation
BBS 3
BBS 4
BBS 5
BBS 6
BBS 7
BBS 8
BBS 9
BBS 10
BBS 11
BBS 12

Autosomal Dominant Medullary Cystic Kidney Disease/Familial Juvenile
      Hyperuricemic Nephropathy/ Glomerulocystic Kidney Disease

ADMCKD1             Tubular BM thickening
                    Tubular atrophy
ADMCKD2/FJHN/       Interstitial fibrosis
GCKD                Salt wasting
                    Small corticomedullary
                      cysts

           Other Diseases With Cystic Renal Phenotype

X-linked            Polycystic kidney pheno-
  orofaciodigital     type with progressive re-
  syndrome 1          nal failure
Autosomal           NPHP phenotype
  recessive
  Alstrom
  syndrome 1

     Disease            Extrarenal Symptoms

             Polycystic Kidney Disease

Autosomal domi-     Liver and pancreatic cysts
  nant PKD1         Intracranial aneurysms
Autosomal domi-
  nant PKD2
Autosomal           Hepatic fibrosis
  recessive         Facial malformations
  PKD               Pulmonary hypoplasia from
                      oligohydramnios
                    Ductal-palate malformation
                      in the liver

        Autosomal Recessive Nephronophthisis

NPHP 1/JBTS 4/      Retinitis pigmentosa
  SLSN 1            Truncal cerebellar ataxia
                    Congenital hepatic fibrosis
                    Ocular motor apraxia type
                      Cogan
NPHP 3/SLSN 3       Retinitis pigmentosa
                    Leber congenital amaurosis
NPHP 4/SLSN 4       Retinitis pigmentosa
NPHP 5/SLSN 5
                    Early onset retinitis pig-
                      mentosa
NPHP 6/JBTS 5/      Retinal degeneration
  SLSN 6/MKS 4      Early onset retinitis pig-
                      mentosa
                    Cerebellar vermis aplasia
                    Leber congenital amaurosis
NPHP 7              Not reported

NPHP 8/JBTS 7/      Retinitis pigmentosa
  MKS 5             Hepatic fibrosis
NPHP 9              Not reported
NPHP 2              Situs inversus
                    Retinitis pigmentosa
                    Cardiac ventricular septal
                      defect

Additional Autosomal Recessive Syndromes Associated With
               Nephronophthisis

JBTS 1              Cerebellar vermis aplasia
                    "Molar tooth" sign
JBTS 2              Polymicrogyria
                    Hypotonia Ataxia
JBTS 3              Mental retardation
                    Rod-cone dysfunction
                    Abnormal eye movements
                    Hyperpnea
JBTS 6/MKS 3        Fibrocystic liver
                    Occipital encephalocele
                    Postaxial polydactyly
                    Cleft lip/palate
                    Heart malformations
MKS 1               Liver fibrosis
                    Occipital encephalocele
                    Postaxial polydactyly
                    Cleft lip/palate
                    Heart malformations
BBS 1
BBS 2               Retinitis pigmentosa
                    Anomalies of distal limb
BBS 3               Obesity
                    Mental retardation
BBS 4               Polydactyly
                    Male hypogenitalism
BBS 5
BBS 6
BBS 7
BBS 8
BBS 9
BBS 10
BBS 11
BBS 12

Autosomal Dominant Medullary Cystic Kidney Disease/Familial Juvenile
      Hyperuricemic Nephropathy/Glomerulocystic Kidney Disease

ADMCKD1             Hypertension
                    Hyperuricemia (gout)
ADMCKD2/FJHN/
GCKD

             Other Diseases With Cystic Renal Phenotype

X-linked            Hydrocephalus
  orofaciodigital   Malformations of face, oral
  syndrome 1          cavity, and digits
Autosomal           Progressive visual impair-
  recessive           ment
  Alstrom           Cone-rod dystrophy and
  syndrome 1          blindness
                    Diabetes mellitus
                    Truncal obesity
                    Acanthosis nigricans
                    Male hypogenitalism
                    Dilated cardiomyopathy
                    Neurosensory deafness

Abbreviations: ADMCKD, autosomal dominant medullary cystic kidney
disease; ADP, adenosine diphosphate; AHI, Abelson helper integration
site; ALMS1, Alstrom syndrome 1; ARL6, ADP ribosylation factor-like 6;
BBS, Bardet-Biedl syndrome; BM, basement membrane; C4orf24, chromosome
4 open reading frame 24; C12orf58, chromosome 12 open reading frame
58; CEP290, centrosomal protein 290 kDa; ESRD, end-stage renal
disease; FABB, flagella-basal body; FJHN, familial juvenile
hyperuricemic nephropathy; GCKD, glomerulocystic kidney disease;
GLIS2, glioma-associated similar protein 2; GTP, guanosine
triphosphate; INVS, inversin; IQCB1, IQ motif containing B1; JBTS,
Joubert syndrome; MKS, Meckel-Gruber syndrome; MKKS,
McKusick-Kaufmann syndrome; NEK8, NIMA-related kinase 8; NIMA, never
in mitosis gene A; NPHP, nephronophthisis; OFD1, orofaciodigital
syndrome 1; PKD, polycystic kidney disease; PKHD1, polycystic kidney
and hepatic disease 1; PTHB1, parathyroid hormone-responsive, B1
protein; RPGRIP1L, retinitis pigmentosa GTPase regulator interacting
protein 1--like; SLSN, Senior-Loken syndrome;TMEM67, transmembrane
protein 67; TRIM32, tripartite motif 32; TTC8, tetratricopeptide
repeat domain protein 8; UMOD, uromodulin.
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Author:Deltas, Constantinos; Papagregoriou, Gregory
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Report
Geographic Code:4EXCY
Date:Apr 1, 2010
Words:13338
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