Arg133Cys Mutation of Notch3 in Two Unrelated Japanese Families with CADASIL.

Abstract

Objective More than 80 unrelated, but all Caucasian, patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), originating from various communities around the world, have been molecularly identified. To clarify the occurrence of CADASILin Orientals, we investigated Japanese families presenting as CADASIL. Methods Weperformed the PCR-SSCPand sequence analyses using genomic DNA,isolated from venous blood of participants under informed consent. Patients Weidentified two unrelated Japanese families with CADASIL,including 5 affected members through 2 generations.Results Each of the affected individuals developed recurrent strokes without risk factors resulting in progressive dementia, pseudobulbar palsy, and gait disturbances which started after the fifth decade of life. Although affected individuals had no vascular risk factors, they showed various degrees of narrowing of retinal arteries. Their MRI/ CTs showed characteristics of the disease; bilateral small infarcts in the thalamus, basal ganglia, brain stem, and deep white matter in addition to the findings of leukoaraiosis. On SPECTimaging, there was severe hypoperfusion in the cortex as well as in the white matter. Ultrastructural studies revealed an abnormal deposition of granular osmiophilic materials (GOM)within the basal lamina of pericytes in muscular capillaries. On PCR-SSCPand sequence analyses, a heterozygous Argl33Cys mutation was present, in the affected individuals, in the exon 4 of Notch3 gene which is the hot spot region for CADASILmutations in Caucasian families. None of the non-affected membersnor the 50 Japanese normal controls revealed this mutation. Conclusion Thus, our results confirm that CADASIL is a geographically widespread disorder caused by a Notch3 mutation. (Internal Medicine 39: 732-737, 2000)

The Association Between the Genetic Variants of the NOTCH3 Gene and Ischemic Stroke Risk

“…The conclusion indicates a heterozygous genotype of Arg133Cys present in CADASIL patients, and, furthermore, this locus is in the exon 4 of NOTCH3 gene, which is a hot spot domain in Caucasian families with CADASIL. This confirms that the occurrence of CADASIL caused by a NOTCH3 mutation is not restricted by geographic position [27]. Because stroke is the clinical and primary symptom of CADASIL, the relevance of NOTCH3 polymorphisms and IS is suspected.…”

Arg332Cys mutation of NOTCH3 gene in the first known Taiwanese family with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

“…Exon 6 mutations were detected in five families, but two of them were not in the codon 332 site. Although uncommon, other mutation regions including exons 2,7,8,9,14,18,19,20, and 22 of Notch3 have been found in Caucasian CADASIL patients [7,8].…”

“…Mutations of the NOTCH3 gene have been identified as the genetic defect underlying CADASIL [3,5,6]. Numerous mutations have been found in Caucasian populations [7,8], but mutation sites other than sites within exons 3, 4, and 5 have not been found in Asians [9][10][11][12][13][14]. Here, we report a Taiwanese family affected with CADASIL who have a NOTCH3 mutation at exon 6 and we characterize their disease in terms of comprehensive clinical and neuroimaging studies.…”

Genotypic and phenotypic spectrum of CADASIL in Japan: the experience at a referral center in Kumamoto University from 1997 to 2014

“…In Japan, where people with a relatively uniform genetic background live in an isolated island country, a number of CADASIL kindreds were reported with different NOTCH3 gene mutations [9][10][11][12][13]. However, in these Japanese CADASIL patients, the spectrum of NOTCH3 mutations and the clinicopathological features, which are quite important for the diagnosis of CADASIL, have not as yet been clarified.…”