title: The CAG repeat at the Huntington disease gene in the Portuguese population: insights into its dynamics and to the origin of the mutation.
abstract: Huntington disease (HD) is caused by an expansion of a CAG repeat. This repeat is a dynamic mutation that tends to undergo intergenerational instability. We report the analysis of the CAG repeat in a large population sample (2,000 chromosomes) covering all regions of Portugal, and a haplotype study of (CAG)n and (CCG)n repeats in 140 HD Portuguese families. Intermediate class 2 alleles represented 3.0% of the population; and two expanded alleles (36 and 40 repeats, 0.11%) were found. There was no evidence for geographical clustering of the intermediate or expanded alleles. The Portuguese families showed three different HD founder haplotypes associated with 7-, 9- or 10-CCG repeats, suggesting the possibility of different origins for the HD mutation among this population. The haplotype carrying the 7-CCG repeat was the most frequent, both in normal and in expanded alleles. In general, we propose that three mechanisms, occurring at different times, may lead to the evolution from normal CAGs to full expansion: first, a mutation bias towards larger alleles; then, a stepwise process that could explain the CAG distributions observed in the more recent haplotypes; and, finally, a pool of intermediate (class 2) alleles more prone to give rise to expanded HD alleles.
authors.affiliation: School of Health Sciences, Life and Health Sciences Research Institute (ICVS), University of Minho, Braga, Portugal.
authors.forename: Maria do Carmo
authors.initials: MDC
authors.lastname: Costa
authors.affiliation: Institute for Molecular and Cell Biology, UnIGENe, Porto, Portugal.
authors.forename: Paula
authors.initials: P
authors.lastname: Magalhães
authors.affiliation: University Fernando Pessoa, Porto, Portugal.
authors.forename: Laura
authors.initials: L
authors.lastname: Guimarães
authors.affiliation: School of Health Sciences, Life and Health Sciences Research Institute (ICVS), University of Minho, Braga, Portugal.
authors.forename: Patrícia
authors.initials: P
authors.lastname: Maciel
authors.affiliation: Institute for Molecular and Cell Biology, UnIGENe, Porto, Portugal.|Department of Populations Studies, ICBAS, University of Porto, 4099-003, Porto, Portugal.
authors.forename: Jorge
authors.initials: J
authors.lastname: Sequeiros
authors.affiliation: Institute for Molecular and Cell Biology, UnIGENe, Porto, Portugal. absousa@icbas.up.pt.|Department of Populations Studies, ICBAS, University of Porto, 4099-003, Porto, Portugal. absousa@icbas.up.pt.
authors.forename: Alda
authors.initials: A
authors.lastname: Sousa
mesh_terms: D000483:Alleles; D005828:Genetics, Population; D006239:Haplotypes; D006801:Humans; D006816:Huntington Disease / Q000235:genetics*; D009154:Mutation; D011174:Portugal; D018911:Trinucleotide Repeats