Analysis of germline mutation spectra at the Huntington's disease locus supports a mitotic [correction of amitotic] mutation mechanism [published erratum appears in Hum Mol Genet 1999 Apr;8(4):717]

Abstract

Trinucleotide repeat disease alleles can undergo 'dynamic' mutations in which repeat number may change when a gene is transmitted from parent to offspring. By typing >3500 sperm, we determined the size distribution of Huntington's disease (HD) germline mutations produced by 26 individuals from the Venezuelan cohort with CAG/CTG repeat numbers ranging from 37 to 62. Both the mutation frequency and mean change in allele size increased with increasing somatic repeat number. The mutation frequencies averaged 82% and, for individuals with at least 50 repeats, 98%. The extraordinarily high mutation frequency levels are most consistent with a mutation process that occurs throughout germline mitotic divisions, rather than resulting from a single meiotic event. In several cases, the mean change in repeat number differed significantly among individuals with similar somatic allele sizes. This individual variation could not be attributed to age in a simple way or to ' cis ' sequences, suggesting the influence of genetic background or other factors. A familial effect is suggested in one family where both the father and son gave highly unusual spectra compared with other individuals matched for age and repeat number. A statistical model based on incomplete processing of Okazaki fragments during DNA replication was found to provide an excellent fit to the data but variation in parameter values among individuals suggests that the molecular mechanism might be more complex.

Hijacking of the mismatch repair system to cause CAG expansion and cell death in neurodegenerative disease

“…Thus, their role in causing expansion is difficult to test. Further, tests of expansion among cell types have not always painted a consistent picture due to the fact that the effects of strand breaks cannot be separated from the effects of replication in proliferating cells [67][68][69][70][71][72][78][79][80]. However, the use of transgenic animals has been particularly informative [70,[80][81][82][83][84][85][86].…”

Molecular analysis and prevalence of Huntington disease in northwestern Iran

“…Therefore, meiotic instability of the HD allele takes place during spermatogenesis (29). In the present study, by analyzing the pedigrees of patients, it was observed that 66% (10/15) of the individuals inherited the mutant allele paternally and 20% (3/15) inherited it maternally.…”

Genetic Modifiers of CAG.CTG Repeat Instability in Huntington's Disease Mouse Models

“…In the two largest cohorts (>250 parent-offspring pairs), the frequency of expansions was estimated to be 52.1% in a multiethnic HD population and 67.3% in the Dutch cohort, whereas only 18.1% and 25.2% contractions were observed, respectively [13,18]. For individuals carrying more than 49 CAG repeats, the mutation rates go up to >95% per generation [14,20]. In all cases, the frequency of expansions always exceeds the frequency of contractions in HD populations.…”