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

The gene causing Huntingtons'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 patlents showing 23 alleles with 11 to 33 repeats. Analyzing the Inherltance of the (CAG)n stretch we found melotic instability for HD alleles ([CAG]40 to [CAG]75) with a mutation frequency of approximately 0.7, while In 431 meloses of normal alleles only two expanslons were Identified. The risk of expansion during spermatogenesis is enhanced compared to oogenesls 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 mosalcism or differences In the repeat lengths were observed In the DNA from different tissues Including brain and lymphocytes of two HD patients indicating mltotic 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.