Mitotic stability and meiotic variability of the (CAG)_n repeat in the Huntington disease gene

Abstract

The gene causing Huntington's disease, an autosomal dominantly inherited, neurodegenerative disorder, has been identified recently. The corresponding mutation is involving an expansion in the number of (CAG)n repeats in the coding region of the Huntington's disease gene on chromosome 4. In this report, we demonstrate the length variation of the repeat in 513 non-HD chromosomes from normal individuals and HD patients showing 23 alleles with 11 to 33 repeats. Analyzing the inheritance of the (CAG)n stretch we found meiotic instability for HD alleles ([CAG]40 to [CAG]75) with a mutation frequency of approximately 0.7, while in 431 meioses of normal alleles only two expansions were identified. The risk of expansion during spermatogenesis is enhanced compared to oogenesis explaining juvenile onset by transmission from affected fathers. Further, the number of (CAG)n copies in an affected individual in relation to the sex of the transmitting parent was evaluated and no significant differences were found. No mosaicism or differences in the repeat lengths were observed in the DNA from different tissues including brain and lymphocytes of two HD patients indicating mitotic stability of the mutation. Therefore, the determination of the repeat number in the DNA of blood lymphocytes is probably representative of all tissues in a patient.

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

“…Indeed, a CAG repeat size change on expanded allele in the range of 36-49 repeats occurs in >70% of transmissions from affected parents to HD children. A similar rate of expansion was found between multiethnic cohorts [13][14][15][16][17][18][19]. 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].…”

Post-Meiotic DNA Damage and Response in Male Germ Cells

“…Several diseases with dynamic mutation, characterized by the expansion over generation of a trinucleotidic repeat (TNRs), are associated with a paternal bias of expansion, such as Huntington disease (HD), spinocerebellar ataxia type 2 and 7 (Cancel et al, 1997;Stevanin et al, 1998;Zühlke et al, 1993). TNRs are microsatellites sequences in coding or non-coding region of the genome.…”

Intergeneration CAG expansion in a Wuhan juvenile-onset Huntington disease family

“…HD is characterized by dynamic mutation of IT15 during the abnormal gene transmitted from parents to the descendants [8,9] . Especially, the paternal transmission tends to cause the length of CAG repeats increasing [10,11] , which in turn results in the genetic anticipation [12,13] , that is, the offspring appear HD symptom at earlier age and with more severe conditions.…”

“…All the five male patients of the third generation developed HD at 33 years old. Therefore, we speculated that the late III 8 …”