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

The gene causing Huntingtons's disease, an autosomal dominantlyInherited, neurodegenerative disorder, has been Identified recently.The corresponding mutation Is Involving an expansion In thenumber of (CAG)_n repeats In the coding region of the Huntington'sdisease gene on chromosome 4. In this report, we demonstratethe length variation of the repeat In 513 non-HD chromosomesfrom normal Individuals and HD patlents showing 23 alleles with11 to 33 repeats. Analyzing the Inherltance of the (CAG)_n stretchwe found melotic instability for HD alleles (CAG]₄₀ to CAG]₇₅)with a mutation frequency of approximately 0.7, while In 431meloses of normal alleles only two expanslons were Identified.The risk of expansion during spermatogenesis is enhanced comparedto oogenesls explaining juvenile onset by transmission fromaffected fathers. Further, the number of (CAG)_n copies In anaffected individual In relation to the sex of the transmittingparent was evaluated and no significant differences were found.No mosalcism or differences In the repeat lengths were observedIn the DNA from different tissues Including brain and lymphocytesof two HD patients indicating mltotic stability of the mutation.Therefore, the determination of the repeat number In the DNAof blood lymphocytes Is probably representative of all tissuesIn a patient.