The Friedreich's ataxia mutation may originate from a premutation and shows size reduction when transmitted from parent to affected child
Journal Contribution ResearchOnline@JCUAbstract
Most trinucleotide repeat mutations cause dominant or X linked neurological disorders and show progressive increase in size from affected parent to affected child, the basis of phenotypic anticipation. Friedreich's ataxia (FA) is a recessive disorder in which gene dysfunction is due to an expansion of a GAA trinucleotide repeat in intron one which reduces mRNA and protein levels. We confirm that the severity of the disorder in our population depends upon the repeat length of the smaller allele, to a point where those with smaller alleles may be mis-diagnosed with other conditions such as spastic paraparesis. Two brothers were found to be heterozygou1; for the expansion and a point mutation (G to T) which leads to G130V. These patients have an atypical clinical phenotype. From studying 81 transmissions.we demonstrate that the repeat number of the expansion in FA usually decreases in size from parent to affected child, and that this affect is particularly marked in the paternal allele. No expanded alleles were found in the range between 22 and 332 trinucleotides with one important exception, a carrier with an intermediate repeat size of approximately 100. When this allele was transmitted to the affected child, the repeat increased in size either probably to 538 or possible to 1036. Analysis of a sperm sample from this carrier showed a major band for the expanded allele of 320 repeats. These data suggest that there may be a premutation for Friedrelch's ataxia carriers, similar to that demonstrated for FraX-A and that expansion occurs in two stages, the first during meiosis followed by a second mitotic expansion.
Journal
American Journal of Human Genetics
Publication Name
American Journal of Human Genetics
Volume
61
ISBN/ISSN
1537-6605
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Suppl
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1
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Cell Press
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