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CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1.

Author(s): I Akiguchi, Y Kawaguchi, M Taniwaki, M Nishimura, M. Aizawa, H Kawakami, S. Katayama, M Inoue, T Okamoto, Diane S. Nakamura

Publication date: 1994-10-31

Journal: Nature genetics

Keywords: Adult, Amino Acid Sequence, Base Sequence, Blotting, Southern, Chromosomes, Human, Pair 14, Cloning, Molecular, Female, Genes, Humans, In Situ Hybridization, Fluorescence, Machado-Joseph Disease, genetics, Male, Middle Aged, Minisatellite Repeats, Molecular Sequence Data, Multigene Family, Nerve Tissue Proteins, Nuclear Proteins, Pedigree, Proteins, Repressor Proteins

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Abstract

We have identified a novel gene containing CAG repeats and mapped it to chromosome 14q32.1, the genetic locus for Machado-Joseph disease (MJD). In normal individuals the gene contains between 13 and 36 CAG repeats, whereas most of the clinically diagnosed patients and all of the affected members of a family with the clinical and pathological diagnosis of MJD show expansion of the repeat-number (from 68-79). Southern blot analyses and genomic cloning demonstrates the existence of related genes. These results raise the possibility that similar abnormalities in related genes may give rise to diseases similar to MJD.

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The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease.

S Andrew, Y Goldberg, B. Kremer … (1993)

Huntington's disease (HD) is associated with the expansion of a CAG trinucleotide repeat in a novel gene. We have assessed 360 HD individuals from 259 unrelated families and found a highly significant correlation (r = 0.70, p = 10(-7)) between the age of onset and the repeat length, which accounts for approximately 50% of the variation in the age of onset. Significant associations were also found between repeat length and age of death and onset of other clinical features. Sib pair and parent-child analysis revealed that the CAG repeat demonstrates only mild instability. Affected HD siblings had significant correlations for trinucleotide expansion (r = 0.66, p < 0.001) which was not apparent for affected parent-child pairs.

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Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1.

H T Orr, M Y Chung, S. Banfi … (1993)

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant disorder characterized by neurodegeneration of the cerebellum, spinal cord and brainstem. A 1.2-Megabase stretch of DNA from the short arm of chromosome 6 containing the SCA1 locus was isolated in a yeast artificial chromosome contig and subcloned into cosmids. A highly polymorphic CAG repeat was identified in this region and was found to be unstable and expanded in individuals with SCA1. There is a direct correlation between the size of the (CAG)n repeat expansion and the age-of-onset of SCA1, with larger alleles occurring in juvenile cases. We also show that the repeat is present in a 10 kilobase mRNA transcript. SCA1 is therefore the fifth genetic disorder to display a mutational mechanism involving an unstable trinucleotide repeat.