title: Two novel mutations in NOTCH3 gene causes cerebral autosomal dominant arteriopathy with subcritical infarct and leucoencephalopathy in two Chinese families.
abstract: OBJECTIVE
  To investigate the genetic pathogenic causes of cerebral autosomal dominant arteriopathy with subcritical infarct and leucoencephalopathy (CADASIL) in two Chinese families, to provide the molecular basis for genetic counseling and antenatal diagnosis.
  
  
  METHODS
  The genetic mutation of gene NOTCH3 of propositus and family members was analyzed in these two CADASIL families by polymerase chain reaction and DNA sequencing technology directly. At the same time, the NOTCH3 gene mutation point of 100 healthy collators was detected, to explicit the pathogenic mutation by function prediction with Polyphen-2 and SIFT.
  
  
  RESULTS
  Both propositus of the two families and patients with symptom were all accorded with the clinical features of CADASIL. It was shown by DNA sequencing that the 19(th) exon [c. 3043 T > A (p.Cys1015Ser)] in gene NOTCH3 of propositus, 2 patients (II3, III7), and a presymptomatic patient (IV1) in Family I all had heterozygosity missense mutation; and the 3(rd) exon [c.316T > G, p. (Cys106Gly)] in gene NOTCH3 of the propositus, a patient (IV3) and two presymptomatic patients (IV5, 6) in Family II all had heterozygosity missense mutation; and no mutations were detected in the 100 healthy collators. It was indicated by analyzing the function prediction that the mutation of [c. 3043 T > A (p.Cys1015Ser)] and [c.316T > G, p. (Cys106Gly)] may both influence encoding protein in NOTCH3. By analysis of the conservatism of mutation point in each species, these two basic groups were highly conserved.
  
  
  CONCLUSIONS
  The heterozygosity missense mutation of 19(th) exon [c. 3043 T > A (p.Cys1015Ser)] and the 3(rd) exon [c.316T > G, p. (Cys106Gly)] in NOTCH3 gene are the new pathogenic mutations of CADASIL, and enriches the mutation spectrum of NOTCH3 gene.
authors.affiliation: Department of Neurology, The Affiliated Provincial Hospital of Anhui Medical University Hefei 230001, China.
authors.forename: Yuyou
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Dermatology, The Affiliated Provincial Hospital of Anhui Medical University Hefei 230001, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Neurology, The Affiliated Provincial Hospital of Anhui Medical University Hefei 230001, China.
authors.forename: Yuanbo
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Neurology, The Affiliated Provincial Hospital of Anhui Medical University Hefei 230001, China.
authors.forename: Guoping
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Dermatology, The Affiliated Provincial Hospital of Anhui Medical University Hefei 230001, China.
authors.forename: Bai
authors.initials: B
authors.lastname: Hu
mesh_terms: D044466:Asian People / Q000235:genetics; D001921:Brain / Q000473:pathology*; D046589:CADASIL / Q000235:genetics* / Q000473:pathology; D002681:China; D004252:DNA Mutational Analysis; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics*
chemical_list: C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D051880:Receptors, Notch
keywords: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoeneephalopathy; NOTCH3 gene; mutation