Pathogenicity of CAG repeat amplification in the androgen receptor

In a recent study, Cram etal. (2000) have investigated CAG repeat numbers in the AR of 92 infertile men and their inheritance in 99 female offspring conceived after intracytoplasmic sperm injection (ICSI). It turned out that a stable inheritance in the female offspring could be detected in more than 95 of the cases investigated. A CAG expansion or contraction of the paternal AR allele was observed only in 4 father-daughter pairs. All alterations were within the normal range of CAG repeat number and no phenotypic consequences were observed. The study indicates a frequency of changes to occur in the order of 5%. The range of repeat numbers for the AR to be stably transmitted is presumably between 15 and 28 CAG. CAG repeats beyond 28 might bear the risk of instability, possibly up to a disease-causing length (Zhang et al. 1994). Single sperm analysis was performed in a patient with spinobulbar muscular atrophy (SBMA) with a CAG repeat number of 47 in the AR (Zhang etal. 1995). The number of CAG repeats equaled the donor's somatic DNA in only 19% of the analyzed sperm, whereas 66% expansion and 15% contractions were observed. The average expansion was approximately 3 repeats ranging from 1 to 25 repeats. These data highlight the instability of CAG repeats, once a distinct threshold is reached.

CAG repeats shift size when inherited paternally, thus influences transmission. However, the molecular basis for the "parent-of-origin effect" association is not known. For Huntingtons' disease (HD) caused by another gene with a CAG repeat expansion, it has recently been shown that mice harboring a mutant HD gene transmit predominantly through the male germ line since the CAG repeat size of the mutant HD gene is different in male and female progeny from identical fathers. Males predominantly expand the repeat, whereas females predominantly contract the repeat (Kovtun et al. 2000). This indicates that CAG expansion is influenced by the gender of the embryo and that X- or Y-linked factors influence repair or replication of DNA in the embryo. Gender dependency in the embryo might offer an explanation why CAG repeats expansion from a premutation to a disease primarily occur through the paternal line.

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