RESUMO
Hereditary sensory neuropathy type I (HSN I) is an autosomal dominant ulceromutilating disorder of the peripheral nervous system characterized by progressive sensory loss. HSN I locus maps to chromosome 9q22.1-22.3 and is caused by mutations in the gene coding for serine palmitoyltransferase long-chain base subunit 1 (SPTLC1). A novel missense mutation in exon 13 of the SPTLC1 gene (c.1160G-->C; p.G387A) in twin sisters with a severe HSN I phenotype is reported.
Assuntos
Aciltransferases/genética , Neuropatias Hereditárias Sensoriais e Autônomas/genética , Esfingosina/análogos & derivados , Acil Coenzima A/metabolismo , Bélgica , Mapeamento Cromossômico , Cromossomos Humanos Par 9/genética , Análise Mutacional de DNA , Progressão da Doença , Éxons/genética , Feminino , Genes Dominantes , Humanos , Pessoa de Meia-Idade , Mutação , Linhagem , Subunidades Proteicas/genética , Serina/metabolismo , Serina C-Palmitoiltransferase , Esfingosina/biossínteseRESUMO
Mutations in the presenilin 1 (PSEN1) gene are an important cause of autosomal dominant Alzheimer's disease (AD). Both in vitro and in vivo experiments showed that PSEN1 mutations increase secretion of amyloid beta42 (Abeta42), the longer and more fibrillogenic isoform of Abeta. We measured secreted Abeta42 in plasma of patients, presymptomatic mutation carriers, and escapees of two extended Belgian early-onset AD families, AD/A and AD/B, with a similar severe phenotype in terms of onset age (mean 35 years), duration of the disease (mean 6.5 years), and pathology. Both families segregate a different missense mutation in PSEN1 located in different parts of the protein: I143T in family AD/A and G384A in family AD/B. A significant increase in Abeta42 concentrations was observed in plasma of mutation carriers in family AD/B, but not in family AD/A. A differential effect of the two PSEN1 mutations on Abeta42 secretion was also detected in conditioned medium of stably transfected HEK293 cells. Both mutations increased Abeta42 secretion significantly; however, the increase was highest for G384A (5.5-fold over wild-type PSEN1), the largest effect observed for missense PSEN1 mutations to date. Although the Abeta42 concentrations measured in vivo and in vitro did not correlate with onset age, a positive correlation was obtained with age in the presymptomatic mutation carriers and a negative correlation with duration of disease in the patients. Our data obtained for PSEN1 mutation carriers suggest that measuring Abeta42 concentrations in plasma will be informative as a diagnostic marker in a limited number of cases.
