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Acadian usher syndrome.

ABSTRACT--The Usher syndromes are clinically and genetically heterogeneous diseases that cause deafness and blindness in humans. The gene for Type 1C Usher syndrome (USH1C) is segregating in a small population of Acadian descendants from southwestern Louisiana. Molecular analyses of DNA samples from affected Acadian families suggest that the USH1C mutation arose approximately 15 generations ago, corresponding to the seventeenth century arrival of the first Acadians in maritime Canada. We are currently employing a positional cloning strategy in an effort to discover the mutated gene that causes Acadian Usher syndrome. This effort marks the first utilization of an indigenous Louisiana population in the explication of a heritable disease in humans.

Key words: Usher syndrome, Acadian, hereditary deafness, genetic disease, review.


The cultural identity developed by the Acadians over the hundred years they inhabited settlements in historic maritime Canada (Acadia) has persisted through their expulsion and dispersal by decree of the British occupants in the mid-eighteenth century and into the lives of their Louisiana descendants on the brink of the twenty-first. (For modern treatments of Acadian history, see Brasseaux 1987, 1991, and 1992) Despite initial refuges in France, Saint-Domingue, and along the eastern seaboard of the United States, the remaining members of many exiled Acadian families found final refuge in Louisiana, where territorial governments beginning in 1765 settled them on the southern Louisiana prairies west of the Atchafalaya River, along the Mississippi River roughly between Baton Rouge and New Orleans, and finally along the banks of Bayou Lafourche as late as 1785. The identity of this Catholic, French-speaking, agrarian population established in Acadia between 1676 and 1755 was perpetuated in these initial Louisiana settlements, and it is this identity that forms the basis of what we today recognize as Cajun culture.

The economic, religious, and linguistic identity of the Acadians is also the basis of the population's cultural cohesiveness, which was intensified geographically by their eventual settlement in such remote areas as the uninhabited prairies of southwestern Louisiana. Having been derived from a small population of about 100 fur trappers and fishermen in Canada in 1604, Acadian descendants spent much of the next 250 years in cultural isolation, until the arrival of railroads across southern Louisiana in the latter half of the nineteenth century forced their integration. The reality of this isolation served as common justification for a large number of dispensations granted by the Church in the eighteenth and nineteenth centuries to allow intermarriage between familial relatives (Bourquard 1980).

In addition to maintaining cultural cohesiveness, intermarriage among early Acadians had consequently maintained and incidentally perpetuated a degree of biological homogeneity as well, a phenomenon that causes a population to exhibit common genetic traits, including disease traits. In an effort to explain the incidence of genetic disorders in contemporary Acadian families, Thurman and DeFraites (1974) statistically show a nonrandom propensity for marriage among individuals with Acadian surnames living in St. Martinville at the time of the 1840 census. This result, which approximates the statistical propensity for second-cousin marriages, is a result that cannot be demonstrated in population data from 1960-1965. Therefore, although the cultural isolation resulting in dispensatory intermarriages has disappeared in the twentieth century, the genetic results of such historical unions remain.

In the latter half of the twentieth century, clinical scientists have clearly recognized the remnants of Acadian cultural isolation through an increased incidence of particular diseases in subpopulations of Acadian descendants, including Friedreich ataxia (Barbeau et al. 1984), Tay-Sachs disease (McDowell et al. 1992), and Usher syndrome (Kloepfer et al. 1966). Individuals affected with such diseases typically appear in genetic clinics, in familial clusters living in historical Acadian villages, or in specialized hospitals for the chronically impaired.

In this report, we present the natural history of the Acadian Usher syndrome population and review the efforts our laboratories have undertaken to discover the mutation that causes this heritable disease. Our efforts mark the first time data derived from individuals of an exclusively Acadian population have been applied to gene discovery and explication of the cause of a genetic disease. Because of the familial basis of their persistent culture, with particular regard to the maintenance of genealogical information, the Acadian population has served as an invaluable resource in our efforts to understand Usher syndrome and the fundamental biology of the tissues it affects.


The Usher syndromes are characterized by multisensory deficits, including both blindness caused by progressive pigmentary retinal degeneration (RD, also known as retinitis pigmentosa) and deafness that is variable in severity (reviewed by Newsome 1988, Samuelson and Zahn 1990). Named for British ophthalmologist Charles Usher (1914) who first noted hereditary transmission among affected families, the Usher syndromes are autosomal recessive in inheritance and are rare in occurrence. Although the frequency of the Usher syndromes is conservatively estimated at 4.4 per 100,000 in the United States (Boughman et al. 1983), the carrier frequency may be as high as 1 in 100 (Vernon 1969), and more than half of the deaf-blind population is believed to be afflicted with a type of Usher syndrome (Boughman et al. 1983).

Investigators recognize three major types of Usher syndromes distinguishable by both the degree of inner ear dysfunction and the onset of RD (reviewed by Keats and Corey 1999). Type I disease is characterized by profound congenital deafness with lack of vestibular function and childhood onset of RD. Individuals with Type II disease exhibit congenital deafness with normal vestibular function and onset of RD typically as late as the second decade. The Type III disease differs from Type II by the progressive nature of the associated hearing loss. Genetic analyses of different populations around the world exhibiting Usher syndrome have revealed the linkage of at least six chromosomal loci to the Type I disease (Kaplan et al. 1992, Kimberling et al. 1992, Smith et al. 1992b, Wayne et al. 1996, Chaib et al. 1997, Wayne et al. 1997), two to the Type II disease (Kimberling et al. 1990, Lewis et al. 1990, Pieke Dahl et al. 1993), and one to the Type III disease (Sankila et al. 1995, Gasparini et al. 1998). This heterogeneity implies that mutations in any of as many as nine different genes in the human genome can cause the clinical phenomenon known as Usher syndrome.


Beginning in 1955, Kloepfer et al. (1966) investigated the hereditary nature of deafness among individuals of a common ancestral ethnicity ("white Acadian stock") derived from the three-parish region of Lafayette, Vermillion, and Acadia. Initially from historical records (1856-1958) at the State School for the Deaf in Baton Rouge and subsequently from genealogical studies of affected individuals, they established a large set of extended families pedigrees that included 70,000 individuals. Among 289 deaf probands in this study, 44 exhibited a syndrome of deafness with RD that showed autosomal inheritance and complete penetrance.

Subsequent genealogical research of individuals in this original Usher syndrome population (Kosar 1983, Pelias et al. 1986) has established that (1) most nuclear families either are of direct Acadian descent or are products of intermarriage with Acadian descendants west of the Atchafalaya Basin; (2) most among those identified in educational facilities for the deaf in New Orleans and Baton Rouge are related to families in the three-parish study region; and (3) most of the affected families are part of a large kindred whose ancestry derives from two emigrant French couples who arrived in Acadia in 1636 (Pelias et al. 1991). These genealogical relationships suggest that the incidence of Usher syndrome among Acadian descendants is caused by a single or at most a small number of genetic mutation(s).

Further clinical study of Acadian families (Smith et al. 1992a), however, revealed that both Types I and II diseases, as well as the possibility of a Type III disease (first suggested by Karjalainen et al. 1985) distinguished by progressive deafness and vestibular hypoactivity, occur among individuals of Acadian descent. This clinical variability supports the genealogical findings that multiple recessive mutations causing Usher syndrome have segregated with the Acadian population. Genetic heterogeneity is also suggested by studies of other Usher syndrome populations around the world, including families indigenous to northwestern France (Larget-Piet et al. 1994). Although these French families are not genealogically related to the Acadians, their natural history as descendants of geographically isolated agrarian villagers is similar. In fact, the original Acadian emigrants derived from historical villages in the same general coastal region of France, and this region was subsequently the site of tent-villages created by the eighteenth-century Parisian government to house those shiploads of Acadians families who sought repatriation following the expulsion from Canada and before resettlement in Louisiana (Brasseaux 1987). These similar histories are good examples that illustrate the power of social and geographical isolation in causing the accumulation of recessive traits in humans, such as Usher syndrome.

The Acadian descendants who exhibit Type I disease, however, are clinically similar, with similar degrees of auditory, vestibular, and visual dysfunction (Smith et al. 1992a). Analysis of DNA samples from these individuals suggests the inheritance of a common defect in a single gene located on the short arm of chromosome 11 (11p; Smith et al. 1992b). The defect in this gene, tentatively called USH1C (and thus the cause of Type 1C disease), is very likely unique in individuals of Acadian ancestry. Recent analysis of a Lebanese family affected by Type I Usher Syndrome (Saouda et al. 1998) also suggests the inheritance of a defective gene on chromosome 11p. Because of the history and genealogical structure of the Acadian study population, however, it is unlikely that the affected Acadian and Lebanese individuals bear the same gene defect. Because non-Acadians are unlikely either to carry or to be affected by the same gene defect, the Type 1C disease has become known as "Acadian" Usher syndrome (DeAngelis et al. 1998).

To date, the Acadian Usher syndrome population numbers about 300 identified individuals. This, of course, represents a small subpopulation of the roughly half-million individuals who can claim Acadian ancestry (Brasseaux 1987). Although the Usher syndromes are rare, we estimate the disease incidence in the Acadian population at about 2.5 times the incidence in the general U.S. population.


Sequential molecular analyses of DNA samples from affected and unaffected individuals using DNA markers on all 22 autosomes (Pelias et al. 1988, Smith et al. 1989, Keats et al. 1992, Smith et al. 1992b, Keats et al. 1994, Marietta et al. 1997) have revealed that most affected individuals of Acadian descent are exclusively homozygous for a small region of the short arm of chromosome 11 (11p15.1-p14). This region contains identifiable DNA markers that have segregated without meiotic recombination in the population of affected Acadian descendants. The statistical correlation between affectedness and nonrecombination (genomic similarity) is a strong indicator that USH1C lies in this candidate genomic region. A consensus genetic map derived from these analyses localizes USH1C to a critical region bounded by the anonymous DNA markers D11S1397 (telomeric) and D11S1310 (centromeric) and containing markers that are nonrecombinant in the Acadian population (Fig. 1). Using contemporary estimates of both the number of (100,000) and average nucleotide length of (30,000 bp) human genes, the genetic map suggests that USH1C could be any of as many as 30 genes that lie in the critical region.



Because of the structure of the Acadian population, a founder effect for the USH1C mutation is suggested. Genetic analysis of DNA samples from individuals affected with Type IC disease suggests the recent origin of a unique mutation in the Acadian population (Nouri et al. 1994), supporting the finding of a common genealogical origin of affected individuals (Kosar 1983, Pelias et al. 1986). In our study of 27 nuclear families with Type IC disease and of Acadian ancestry (Keats et al. 1992), nearly all individuals possessed the same profile of genomic markers from chromosome 11p15.1-p14, suggesting that a single mutation is responsible for all cases of Acadian Usher syndrome. The closest relationship among parents in this study was third cousins. Common linkage to these genomic markers, together with the genealogical relationships among individuals which similarly inherit them, suggest that the age of the USH1C mutation is approximately fifteen generations. This estimate places the USH1C common ancestor (the "founder") among the first French emigrants to arrive in Acadia in 1604. Therefore, the USH1C mutation was already established in the Acadian population before their emigration to Louisiana following the expulsion that began in 1755.


In an effort to develop genomic reagents necessary to discover USH1C among the number of candidate genes predicted by the genetic map, we (DeAngelis et al. 1998) and others (Ayyagari et al. 1996, Higgins et al. 1998) have identified sets of large human genomic clones (yeast and bacterial artificial chromosomes [YAC's and BAC's]) that contain the USH1C critical region. Such clone sets (called contigs) provide contiguous containment of genomic regions, as well as (1) accurate estimates of the size of critical regions based upon the physical sizes of constituent clones and (2) continuous sources of cloned DNA necessary for the application gene discovery techniques.

A consensus contig consisting of two YAC's, clones yMY776e7 and yMY996e8 (about 0.8 and 2.0 Mbp respectively) was sufficient to contain all DNA markers from genetic mapping known to bound and be contained within the USH1C critical region. In addition, we have developed a BAC contig of the critical region (DeAngelis et al. 1998) consisting of 60 clones. The high resolution of the USH1C BAC contig has not only established a more accurate chromosomal order for the nonrecombinant markers (telomere-D11S921-D11S1228-D11S4099-D11S1890-centromere; Fig. 1) but has also more accurately established the physical size of the critical region at less than 400 kb. The nucleotide length of this physical map suggests that a conservative estimate of the number of USH1C candidates is 4-6 genes.


Genes encoding proteins associated with vision or hearing physiology are obvious candidate genes for USH1C, but to date no genes suggestive of such sensory involvement have been mapped to 11p15.1-p14. The KCNC1 gene, which encodes a component of a voltage-gated potassium channel, has been mapped to the USH1C critical region (Marietta et al. 1997). Analysis of the coding region of the KCNC1 gene, however, has revealed no mutations in individuals affected with Type IC disease. Although the regulatory regions of the KCNC1 gene must be analyzed for mutations before unequivocably dispelling the gene's candidacy as USH1C, it is apparent that structural alterations in the KCNC1 protein are not the cause of Type IC Usher syndrome.

Using data and clones from our physical maps of the USH1C critical region, we have localized the human NEFA gene to 11p15.1-p14 (DeAngelis et al. 1998). NEFA encodes a C[a.sup.2+]- and DNA-binding protein that has been previously cloned (Barnikol-Watanabe et al. 1994). Nucleotide sequence analysis of the coding region of NEFA, however, has likewise revealed no mutations in individuals affected with Type IC disease (DeAngelis et al. 1998, Higgins et al. 1998).

The USH1C gene is one of currently six genes predicted to cause Type I disease (Kaplan et al. 1992, Kimberling et al. 1992, Smith et al. 1992b, Wayne et al. 1996, Chaib et al. 1997, Wayne et al. 1997). It is conceivable that some or all of the proteins encoded by these genes either (1) share homology and therefore exhibit amino acid sequence similarity or (2) function coordinately in vision and hearing physiology. This reasoning could explain how the loss of any of these protein functions to mutation would cause the same clinical phenomena. For this reason, it becomes important to use genetic information from any of the six loci linked to Type I disease in efforts to find genes causing the others. Such an opportunity became available in 1995 with the discovery that a defective myosin VIIa gene caused the non-Acadian Type IB Usher syndrome (Weil et al. 1995). This nonmuscle myosin gene (formerly named USH1B) maps to the long arm of chromosome 11 at 11q13, and both the q13 and p15.1-p14 regions share a common orthologous locus in region F of mouse chromosome 7 (Nadeau et al. 1992, Eppig and Nadeau 1995). Because of this common evolutionary derivation, we hypothesized that both USH1B and USH1C were duplications of an ancestral mouse myosin gene. However, using nucleotide sequence information from the myosin VIIa gene, hybridization- and amplification-based analyses of clones comprising the USH1C contigs by us (unpublished data) and others (Ayyagari et al. 1996) have revealed no evidence of myosin homologues in the USH1C critical region. Further, no genes encoding proteins known to interact with myosins have been mapped to the USH1C critical region. These results reduce the likelihood that USH1C and USH1B are related structurally, and therefore we conclude that USH1C is not likely a myosin gene.

In an effort to facilitate discovery of genes in the USH1C critical region, we have recently begun a large-scale sequencing strategy on components of our high-resolution BAC contig. This project involves (1) converting BAC components into small subclones suitable for automated sequencing, (2) computer-based assembly of individual subclone nucleotide sequence into a continuous and consensus nucleotide sequence, and (3) identification of putative genes by either computer-based similarity searches with genes and expressed sequences in the world-wide databases (Altschul et al. 1990) or by computer-based gene prediction using consensus genomic landmarks (Uberbacher et al. 1996). Following the discovery of putative genes from the sequencing data (DeAngelis 1999), we are analyzing the nucleotide sequence of these candidate genes in DNA samples from individuals affected with Type lC disease and from unaffected individuals. Difference in the nucleotide sequence obtained from these two groups suggests a mutation and therefore the likely cause of Type IC Usher syndrome.


Acadian (Type IC) Usher syndrome occurs in a small subpopulation of Acadian descendants deriving from a three-parish region in southwestern Louisiana. The mutation causing the disease likely arose in a common ancestor who lived in Acadia in the early seventeenth century.

Although the Acadian expulsion that began in 1755 results in a dispersion of modern-day Acadian descendants, particularly in Canada and across the U.S. eastern seaboard in addition to Louisiana, it is not surprising to find an autosomal recessive disease like Type IC Usher syndrome indigenous to a single descendant subpopulation. At the pre-expulsion population growth rate of 100% every 25 years in Acadia, which assumes historic infant and child mortality rates of 28% and 50%, respectively (Clark 1968, Griffiths 1973), we can expect the USH1C common ancestor to have accrued less than 100 descendants by 1755, and only a fraction of these descendants could be carriers of the USH1C mutation. From this fraction, as many as 20%-50% would have perished due to starvation, exposure, and disease during their attempted resettlement. And finally, although estimates of the pre-expulsion Acadian population are as high as 18,000, only about 1.1-1.6% of this population founded the original southwestern Louisiana Acadian settlements in 1766 (Brasseaux 1991), from which the Acadian Usher syndrome subpopulation derives. Therefore, the frequency of the mutated allele as it emerged from Acadia beginning in 1755 was likely low, and from this low number most if not all surviving carriers settled in the initial Acadian settlements of southwestern Louisiana in 1766.

The bottleneck effect caused by the Acadian expulsion is a major contributing factor in the exclusivity of the mutation that causes Type IC disease to southwestern Louisiana ancestry. The increased incidence of the disease in the Acadian population is also the product of the population's cultural and geographical isolation in the seventeenth through mid-nineteenth centuries. For these reasons, we can expect the genetic homogeneity of the Acadian people to reveal other unique traits upon investigation. The mutation that causes Acadian Usher syndrome identifies the first example of a genetic trait that is purely Acadian.

Using data and DNA samples that derive from family information collected as early as 1955, our laboratories have undertaken the ambitious project of determining the genetic cause of Acadian Usher syndrome. In the 44 years that have bridged genealogy with gene discovery, we are on the brink of determining the causative mutation, the first such discovery among heritable diseases of indigenous Louisiana populations.

Successful discovery of the USH1C mutation in the Acadian population will not only allow the development of precision DNA tests to determine carrier status and to facilitate prenatal diagnosis, but discovery of the USH1C gene will provide a clear indicator of which therapies are most suitable to remediate the disease. Further, discovery of USH1C will (1) likely facilitate discovery of the genes that cause other types of Usher syndrome and (2) provide investigators with important insight into the cellular mechanisms shared by the two major senses in humans.

Although the potential scientific and clinical benefits of gene discovery in Acadian Usher syndrome will likely benefit both other Usher syndrome populations and the unaffected world population as a whole, it is important to acknowledge the invaluable resources provided by the Louisiana Acadian population. The cultural cohesiveness of the Acadians has not only preserved family structure for two and a half centuries but has also created an immense genealogical legacy. It is their selfless nature that has facilitated access to that family data, despite risks of inadvertently and unintentionally helping perpetuate the stereotype of a rural, inbred people.

The Usher syndromes are rare, heritable diseases that occur in populations around the world. Although occurring at an incidence higher than the general U.S. population, only a small subpopulation of Louisiana Acadians bears this disease. Their contribution to modern medical science will be immeasurable.


The authors acknowledge the contributions of Dr. Prescott Deininger (Tulane University Cancer Center, New Orleans, Louisiana), Dr. Mark Batzer (LSU Health Sciences Center, New Orleans, Louisiana), and Dr. Margaret DeAngelis (Harvard Medical School, Boston, Massachusetts) for their contributions to genetic analysis and USH1C discovery. For critical review of the manuscript, we thank Amy Eliser, Matt Poirer, Ryan Walker, Sean Graham, and Lisa Segura (all of Nicholls State University). Preparation of this manuscript was supported by a grant (to J.P.D.) from the Louisiana Educational Quality Support Fund.


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John P. Doucet

Molecular Genetics Section
Department of Biological Sciences
Nicholls State University
Thibodaux, LA 70310

Mary Z. Pelias and Bronya J. B. Keats

Department of Biometry and Genetics
Louisiana State University Health Sciences Center
New Orleans, LA 70112
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Author:Doucet, John P.; Pelias, Mary Z.; Keats, Bronya J. B.
Publication:The Proceedings of the Louisiana Academy of Sciences
Geographic Code:1U7LA
Date:Jan 1, 1999
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