Contribution of DNA Sequence and CAG Size to Mutation Frequencies of Intermediate Alleles for Huntington Disease: Evidence from Single Sperm Analyses
| Autor: | F. Richards, G van den Engh, David Sillence, Brooke N. Bourdélat-Parks, Cheryl R. Greenberg, K. Nichol, Y P Goldberg, Michael R. Hayden, E. Almqvist, Leah LaTray, M. R. Hughes, H Telenius, B. R. Haddad, Elizabeth Ives, Sean Chong |
|---|---|
| Rok vydání: | 1997 |
| Předmět: |
Male
congenital hereditary and neonatal diseases and abnormalities Genetic counseling Population Biology Germline Trinucleotide Repeats Huntington's disease mental disorders Genetics medicine Humans Allele education Molecular Biology Gene Alleles Genetics (clinical) education.field_of_study Haplotype DNA General Medicine medicine.disease Spermatozoa nervous system diseases Huntington Disease Haplotypes Mutation Mutation (genetic algorithm) |
| Zdroj: | Human Molecular Genetics. 6:301-309 |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/6.2.301 |
| Popis: | New mutations for Huntington disease (HD) arise from intermediate alleles (IAs) with between 29 and 35 CAG repeats that expand on transmission through the paternal germline to 36 CAGs or greater. Using single sperm analysis, we have assessed CAG mutation frequencies for four IAs in families with sporadic HD (IANM) and IAs ascertained from the general population (IAGP) by analyzing 1161 single sperm from three persons. We show that IANM are more unstable than IAGP with identical size and sequence. Furthermore, comparison of different sized IAs and IAs with different sequences between the CAG and the adjacent CCG tracts indicates that DNA sequence is a major influence on CAG stability. These studies provide estimates of the likelihood of expansion of IANM and IAGP to > or = 36 CAG repeats for these individuals. For an IA with a CAG of 35 in this family with sporadic HD, the likelihood for siblings to inherit a recurrent mutation > or = 36 CAG is approximately 10%. For IAGP of a similar size, the risk of inheriting an expanded allele of > or = 36 CAG through the paternal germline is approximately 6%. These risk estimates are higher than previously reported and provide additional information for counselling in these families. Further studies on persons with IAs will be needed to determine whether these results can be generalized to other families. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|