Gonosomal mosaicism in myotonic dystrophy patients: involvement of mitotic events in (CTG)n repeat variation and selection against extreme expansion in sperm.
Myotonic dystrophy ( DM ) is caused by abnormal expansion of a polymorphic ( CTG ) n repeat , located in the DM protein kinase gene . We determined the ( CTG ) n repeat lengths in a broad range of tissue DNAs from patients with mild , classical , or congenital manifestation of DM . Differences in the repeat length were seen in somatic tissues from single DM individuals and twins . Repeats appeared to expand to a similar extent in tissues originating from the same embryonal origin . In most male patients carrying intermediate- or small-sized expansions in blood , the repeat lengths covered a markedly wider range in sperm . In contrast , male patients with large allele expansions in blood ( > 700 CTGs ) had similar or smaller repeats in sperm , when detectable . Sperm alleles with > 1 , 000 CTGs were not seen . We conclude that DM patients can be considered gonosomal mosaics , i . e e . , combined somatic and germ-line tissue mosaics . Most remarkably , we observed multiple cases where the length distributions of intermediate- or small-sized alleles in fathers sperm were significantly different from that in their offsprings blood . Our combined findings indicate that intergenerational length changes in the unstable CTG repeat are most likely to occur during early embryonic mitotic divisions in both somatic and germ-line tissue formation . Both the initial CTG length , the overall number of cell divisions involved in tissue formation , and perhaps a specific selection process in spermatogenesis may influence the dynamics of this process . A model explaining mitotic instability and sex-dependent segregation phenomena in DM manifestation is discussed
