Identification of a Known Mutation in Notch 3 in Familiar CADASIL in China

Abstract

BackgroundCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited disease leading to recurrent ischemic stroke and vascular dementia. Numerous mutations in the 23 exons of the NOTCH3 gene have been reported to cause CADASIL in Caucasian populations, but the full spectrum of genetic changes leading to this disease is yet to be known and, especially, very few reports are available on CADASIL in Asian populations.Methods and ResultsWe genotyped members of a 5-generational Han Chinese family with CADASIL patients and identified an R133C mutation in the NOTCH3 gene. Clinical analysis demonstrated that the penetrance of the mutation was not complete. Five of the mutation carriers, not exposed to the known vascular risk factors, did not show any clinical feature of CADASIL, suggesting the importance of environmental factors to the development of this disease.ConclusionsMembers of a 5-generational Han Chinese family with CADASIL patients had an R133C mutation in the NOTCH3 gene but only individuals exposed to known vascular risk factors developed CADASIL.

The genetic spectrum and the evaluation of CADASIL screening scale in Chinese patients with NOTCH3 mutations

“…Eight studies described mainland Chinese patients with CADASIL caused by NOTCH3 gene mutation [4,7,9,[11][12][13][14][15][16]. We performed clinical and genetic reanalysis of CADASIL patients in mainland China using the data from our study and those in other studies.…”

“…The total CADASIL cases confirmed by genetic mutation and/or pathological examination had reached 129 cases (65 males and 64 females) from 73 unrelated families in the last 10 years [4,7,9,[11][12][13][14][15][16]. There were 122 with autosomal dominant inheritance while seven were sporadic cases.…”

“…There has been a simple and sufficiently accurate screening scale used to select patients with high suspicion of CADASIL before genetic testing in western countries [10]. However, the accuracy of the scale in Chinese populations may require validation, considering the difference in clinical manifestation and neuroimaging features [4,7,9,[11][12][13][14][15][16].…”

Characterization of variations in IL23A and IL23R genes: possible roles in multiple sclerosis and other neuroinflammatory demyelinating diseases

“…In order to make the present work consistent with the 1975 Declaration of Helsinki, we obtained a written informed consent from each participant or their guardian, and this work also was approved by the Ethics Committee of Harbin Medical University. We also confirm that all experiments were performed in accordance with relevant guidelines and regulations[31]. Medical histories of the enrolled participants were recorded in detail, and the participants also received physical and neurological system examination.…”

Clinical variability of the cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy phenotype in two siblings of a large family showing the same mutation

“…The mutation we uncovered in two siblings of this family results from the substitution of arginine to cysteine at codon 133 (Arg133Cys); it represents a single base alteration occurring on the NOTCH3 gene. Such a mutation is not unknown to authors referring to CADASIL cases; in fact, Scottish and Chinese scholars have referred to it in two papers, with the second group of authors concluding that the penetrance of the mutation was not complete, and that only individuals exposed to known vascular risk factors develop the disease 11,12. However, this mutation was not noted in other large-scale studies, nor in a study of 28 Italian families with NOTCH3 mutations, nor in another larger study of 65 families: the British CADASIL prevalence study 13,14…”