RESUMO
AIM: To characterize clinical features and mutation spectrum in Chinese patients with CADASIL. METHODS: We collected 261 clinically suspected Chinese CADASIL patients from three hospitals located in different regions of China. Sanger sequencing is performed to screen the exons 2 to 24 of NOTCH3 gene. Clinical and genetic data were retrospectively studied. Haplotype analyses were performed in patients carrying p.Arg544Cys and p.Arg607Cys, respectively. RESULTS: A total of 214 patients were finally genetically diagnosed as CADASIL, with 45 known NOTCH3 mutations and a novel c.1817G>T mutation. We found that patients carrying p.Arg607Cys or p.Arg544Cys mutation located in exon 11 occupied nearly 35% in our mutation spectrum. In retrospectively study of clinical data, we found a higher number of patients having cognitive impairment and a lower number of patients having migraine with aura. Furthermore, we identified that patients carrying mutations in exon 11 seemed to experience a later disease onset (p=6.8×10-5 ). Additionally, a common haplotype was found in patients from eastern China carrying p.Arg607Cys, and the patients from Fujian carrying p.Arg544Cys shared the same haplotype with patients from Taiwan carrying p.Arg544Cys. CONCLUSIONS: These findings broaden the mutational and clinical spectrum of CADASIL and provide additional evidences for the existence of founder effect in CADASIL patients.
Assuntos
CADASIL/genética , Mutação/genética , Receptor Notch3/genética , Adulto , Idade de Início , Arginina/genética , Povo Asiático/genética , CADASIL/fisiopatologia , Cisteína/genética , Éxons/genética , Feminino , Estudos de Associação Genética , Células HEK293 , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , TransfecçãoRESUMO
BACKGROUND: TARDBP mutations have been reported in patients with amyotrophic lateral sclerosis (ALS) in different populations except Chinese. The present aim is to investigate the association between TARDBP mutations and Chinese patients with ALS. METHODS: 71 SALS patients and 5 FALS families with non-SOD1 mutations were screened for TARDBP mutations via direct sequencing. RESULTS: A novel heterozygous variation, Ser292Asn (875G>A), was identified in the proband and 4 asymptomatic relatives including the children of the dead patient from a FALS family. Thus the dead patient, the proband's brother, was speculated to carry Ser292Asn though his sample was unavailable to the detection. This variation was not found in 200 unrelated control subjects. A homology search of the TDP-43 protein in different species demonstrated that it was highly conserved. Also, it was predicted to be deleterious to protein function with SIFT-calculated probabilities of 0.00. Therefore, Ser292Asn is predicted to be a pathogenic mutation. In addition, we have found two silent mutations (Gly40Gly and Ala366Ala) and one novel polymorphism (239-18t>c). CONCLUSIONS: The present data have extended the spectrum of TARDBP mutations and polymorphisms, and supported the pathological role of TDP-43 in Chinese ALS patients.
