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Let's repeat: mutation gums up brain cells.


In most genetic disorders, the function of the gene that's mutated determines the symptoms of the disease. For the unusual kind of mutation that causes Huntington's disease Huntington's disease
n.
See hereditary chorea.
 and several similar brain disorders, however, the identity of the gene affected may not matter much.

That's the message emerging from studies of mutant mice created by Peter J. Detloff of the University of Alabama at Birmingham and his colleagues.

The researchers investigate disorders caused when a brief DNA sequence known as a CAG CAG - Cagliari, Sardinia, Italy - Elmas (Airport Code)
CAG - California Association for the Gifted
CAG - Call Accounting Gateway (Telcordia)
CAG - Canadian Association of Gastroenterology (Association Canadienne de Gastroenterologie)
CAG - Canadian Association on Gerontology (Association Canadienne de Gérontologie)
CAG - Cancer Assessment Group (EPA)
CAG - Carcinogen Assessment Group
CAG - Carcinogenic Assessment Group
CAG - Carp Anglers Group
 repeat occurs an abnormally large number of times in a gene's usual sequence. A half dozen or so neurodegenerative neurodegenerative /neu·ro·de·gen·er·a·tive/ (-de-jen´er-ah-tiv) relating to or marked by nervous degeneration.

neu·ro·de·gen·er·a·tive (nr
 diseases stem from an excess of CAG repeats. Huntington's disease, for example, results when a certain gene harbors about 40 or more CAG repeats (SN: 6/10/95, p. 360).

Excess CAG repeats in a given gene add extra copies of the amino acid glutamine
Glu
A nonessential amino acid that occurs widely in proteins and blood and other tissue and is metabolized to yield urinary ammonia. Also called glutaminic acid.
 to the protein encoded by the gene. Detloff and other investigators have wondered whether almost any protein burdened with additional glutamines would cause a neurodegenerative disease or whether CAG repeats do their damage only in the context of specific genes.

The scientists engineered a strain of mice that has 146 extra CAG repeats in a gene that encodes hypoxanthine hypoxanthine /hy·po·xan·thine/ (-zan´then) a purine base formed as an intermediate in the degradation of purines and purine nucleosides to uric acid and in the salvage of free purines. Complexed with ribose it is inosine.

hy·po·xan·thine (h
 phosphoribosyltransferase (HPRT HPRT - Hypoxanthine Phosphoribosyltransferase), an enzyme used by all cells. "You produce a full-length HPRT protein plus the added glutamines," says Detloff. The gene is active in brain cells, but the scientists had no reason to suspect that mutations in it would cause any problems. Mice with a disabled copy of the gene are essentially normal, says Detloff.

The addition of CAG repeats produced a neurological disorder in the mice that resembles aspects of CAG repeat diseases in humans, the investigators report in the Dec. 12 Cell. As the altered mice age, they begin to suffer more seizures than normal mice. Moreover, while mice generally live 2 years or more, none of the mutant mice survived more than 53 weeks.

Finally, Detloff and his colleagues found that the glutamine-laden HPRT proteins accumulate abnormally, forming clumps in the nuclei of the animals' brain cells. Similar deposits occur in human CAG repeat disorders and may trigger brain cell dysfunction and eventual death (SN: 8/16/97, p. 102).

Curiously, the researchers did not find evidence of abnormal brain cell death in their mice. "You can get the symptoms of the disease before the cells are dying," says Richard M. Myers of Stanford University School of Medicine.

These findings bolster the belief that the illnesses caused by extra CAG repeats stem primarily from a mutated protein's additional glutamines, says Myers. Scientists suspect that the long glutamine stretch of one protein may stick to that of another, causing a gradual buildup into the clumps seen inside nuclei.

If this feature is common to all CAG repeat disorders, it raises the possibility that a single drug that inhibits the binding of glutamine stretches would offer a treatment for the illnesses, says Detloff.
COPYRIGHT 1997 Science Service, Inc.
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 1997, Gale Group. All rights reserved. Gale Group is a Thomson Corporation Company.

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Title Annotation:mutated proteins with additional glutaminies cause excess CAG repeats in genes that result in some brain disorders
Author:Travis, John
Publication:Science News
Article Type:Brief Article
Date:Dec 20, 1997
Words:489
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