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Germline mutational dynamics in myotonic dystrophy type 1 males

Allele length and age effects

From the Servei de Genètica (Drs. Martorell and Baiget), Hospital de Sant Pau, Barcelona, Spain; Servei de Neurología (Dr. Gámez), Hospital de la Vall d’Hebrón, Barcelona, Spain; Institute of Biomedical and Life Sciences (Drs. Cayuela and Monckton, F.K. Gould and J.P. McAbney), University of Glasgow, UK; and Department of Neurology (Dr. Ashizawa), University of Texas Medical Branch, Galveston, TX.

Address correspondence and reprint requests to Dr. Loreto Martorell, Servei de Genètica, Hospital de Sant Pau, Pare Claret 167, 08025 Barcelona, Spain; e-mail: mmartorells{at}hsp.santpau.es

Background: The CTG repeat expansion causing myotonic dystrophy type 1 is unstable in the germline, and frequent intergenerational length changes are observed, giving rise to the unusual genetics of the disorder. The repeat is also somatically unstable, and expanded alleles accumulate throughout life, thus compromising simple measures of intergenerational stability.

Objective: To gain a better understanding of the intergenerational dynamics of the DM1 repeat in the male germline.

Methods: We used sensitive small pool PCR procedures to analyze sperm and somatic DNA from 22 DM1 men of different ages, CTG repeat length, and clinical form.

Results: High levels of repeat length variation heavily biased toward further expansions were observed in the sperm of all DM1 men. Progenitor allele length was revealed as a major modifier of interindividual variation, with the largest length changes observed for premutation and protomutation alleles and the highest frequency of contractions in full mutation alleles. However, despite clear increases in the degree of somatic mosaicism, no differences were observed in replicate sperm samples obtained from two men during a 4-year period.

Conclusions: Progenitor allele length is a major modifier of the mutational dynamics of the DM1 repeat in the male germline, but surprisingly age is not. Therefore, other as yet unidentified modifiers must be responsible for the considerable residual interindividual variation that cannot be accounted for by these factors.

Received April 4, 2003. Accepted in final form September 24, 2003.

Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the January 27 issue to find the title link for this article.

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