RESUMO
Spinocerebellar ataxia type 17 (SCA17) is caused by expansion of a CAG/CAA repeat in the TBP gene. Most pathogenic alleles are interrupted and are stably transmitted from parent to offspring without anticipation. We identified three SCA17 families with expansion of uninterrupted alleles, thus greatly increasing the number of known intergenerational transmissions of such alleles. We found that uninterrupted SCA17 alleles are unstable, associated with anticipation, and show a paternal expansion bias that increases with age. Even small increments in repeat length resulted in inordinate increases in anticipation. Anticipation was also associated with childhood presentation. Sequencing of all SCA17 alleles is required for effective genetic counseling.
Assuntos
Antecipação Genética , Ataxias Espinocerebelares/genética , Proteína de Ligação a TATA-Box/genética , Expansão das Repetições de Trinucleotídeos/genética , Adolescente , Adulto , Idade de Início , Alelos , Criança , Progressão da Doença , Feminino , Humanos , Masculino , México , Pessoa de Meia-Idade , Linhagem , Distribuição por Sexo , Ataxias Espinocerebelares/diagnósticoRESUMO
Dominant ataxias show wide geographic variation. We analyzed 108 dominant families and 123 sporadic ataxia patients from Mexico for mutations causing SCA1-3, 6-8, 10, 12, 17 and DRPLA. Only 18.5% of dominant families remained undiagnosed; SCA2 accounted for half (45.4%), followed by SCA10 (13.9%), SCA3 (12%), SCA7 (7.4%), and SCA17 (2.8%). None had SCA1, 6, 8, 12 or DRPLA. Among sporadic cases, 6 had SCA2 (4.9%), and 2 had SCA17 (1.6%). In the SCA2 patients we identified 6 individuals with the rare (CAG)(33) allele, 2 of whom showed early onset ataxia. The distribution of dominant ataxia mutations in Mexicans is distinct from other populations.
Assuntos
Canais de Cálcio/genética , Genes Dominantes , Ataxias Espinocerebelares/epidemiologia , Ataxias Espinocerebelares/genética , Feminino , Humanos , Masculino , México/epidemiologia , Mutação , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Linhagem , Expansão das Repetições de Trinucleotídeos/genéticaRESUMO
Friedreich ataxia accounts for approximately 75% of European recessive ataxia patients. Approximately 98% of pathogenic chromosomes have large expansions of a GAA triplet repeat in the FRDA gene (E alleles), and strong linkage disequilibrium among polymorphisms spanning the FRDA locus indicates a common origin for all European E alleles. In contrast, we found that only 14 of 151 (9.3%) Mexican Mestizo patients with recessive ataxia were homozygous for E alleles. Analysis of polymorphisms spanning the FRDA locus revealed that all Mestizo E alleles had the common European haplotype, indicating that they share a single origin. Genetic admixture levels were determined, which revealed that the relative contributions to the Mestizo FRDA gene pool by Native American and European genes were 76-87% and 13-24%, respectively, commensurate with the observed low prevalence of Friedreich ataxia in Mestizos. This indicates that Friedreich ataxia in Mexican Mestizos is due to genetic admixture of European mutant FRDA genes in the Native American gene pool that existed prior to contact with Europeans.