RESUMO
The instability of the CAG repeat size of the HD gene when transmitted intergenerationally has critical implications for genetic counseling practices. In particular, CAG repeats between 27 and 35 have been the subject of debate based on small samples. To address this issue, we analyzed allelic instability in the Venezuelan HD kindreds, the largest and most informative families ascertained for HD. We identified 647 transmissions. Our results indicate that repeats in the 27-35 CAG range are highly stable. Out of 69 transmitted alleles in this range, none expand into any penetrant ranges. Contrastingly, 14% of alleles transmitted from the incompletely penetrant range (36-39 CAGs) expand into the completely penetrant range, characterized by alleles with 40 or more CAG repeats. At least 12 of the 534 transmissions from the completely penetrant range contract into the incompletely penetrant range of 36-39 CAG repeats. In these kindreds, none of the individuals with 27-39 CAGs were symptomatic, even though they ranged in age from 11 to 82 years. We expect these findings to be helpful in updating genetic counseling practices.
Assuntos
Família , Aconselhamento Genético , Doença de Huntington/genética , Expansão das Repetições de Trinucleotídeos , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Alelos , Criança , Feminino , Humanos , Proteína Huntingtina , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Penetrância , Venezuela , Adulto JovemRESUMO
BACKGROUND: The major determinant of age of onset in Huntington's disease is the length of the causative triplet CAG repeat. Significant variance remains, however, in residual age of onset even after repeat length is factored out. Many genetic polymorphisms have previously shown evidence of association with age of onset of Huntington's disease in several different populations. OBJECTIVE: To replicate these genetic association tests in 443 affected people from a large set of kindreds from Venezuela. METHODS: Previously tested polymorphisms were analysed in the HD gene itself (HD), the GluR6 kainate glutamate receptor (GRIK2), apolipoprotein E (APOE), the transcriptional coactivator CA150 (TCERG1), the ubiquitin carboxy-terminal hydrolase L1 (UCHL1), p53 (TP53), caspase-activated DNase (DFFB), and the NR2A and NR2B glutamate receptor subunits (GRIN2A, GRIN2B). RESULTS: The GRIN2A single-nucleotide polymorphism explains a small but considerable amount of additional variance in residual age of onset in our sample. The TCERG1 microsatellite shows a trend towards association but does not reach statistical significance, perhaps because of the uninformative nature of the polymorphism caused by extreme allele frequencies. We did not replicate the genetic association of any of the other genes. CONCLUSIONS: GRIN2A and TCERG1 may show true association with residual age of onset for Huntington's disease. The most surprising negative result is for the GRIK2 (TAA)(n) polymorphism, which has previously shown association with age of onset in four independent populations with Huntington's disease. The lack of association in the Venezuelan kindreds may be due to the extremely low frequency of the key (TAA)(16) allele in this population.
Assuntos
Doença de Huntington/epidemiologia , Doença de Huntington/genética , Polimorfismo de Nucleotídeo Único , Receptores de N-Metil-D-Aspartato/genética , Transativadores/genética , Idade de Início , Apolipoproteínas E/genética , Desoxirribonucleases/genética , Frequência do Gene , Humanos , Proteína Huntingtina , Repetições de Microssatélites , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Proteínas de Ligação a Poli-ADP-Ribose , Receptores de Ácido Caínico/genética , Fatores de Elongação da Transcrição , Expansão das Repetições de Trinucleotídeos/genética , Proteína Supressora de Tumor p53/genética , Ubiquitina Tiolesterase/genética , Venezuela , Receptor de GluK2 CainatoRESUMO
The PAX6 gene is expressed at high levels in the developing eye and cerebellum and is mutated in patients with autosomal dominant aniridia. We have tested the role of PAX6 mutations in three families with Gillespie syndrome, a rare autosomal recessive condition consisting of partial aniridia, cerebellar ataxia, and mental retardation. Single-strand conformational polymorphism analysis of affected individuals revealed no alteration of PAX6 sequences. In two families, the disease trait segregates independently from chromosome 11p markers flanking PAX6. We conclude that Gillespie syndrome is genetically distinct from autosomal dominant aniridia.