A Novel Cysteine-Sparing NOTCH3 Mutation in a Chinese Family with CADASIL

Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an adult onset cerebral small vessel disorder caused by the mutations of the neurogenic locus notch homolog protein 3 (NOTCH3) gene. The extracellular part of NOTCH3 is composed of 34 epidermal growth factor-like (EGF-like) repeat domains. Each EGF-like domain is rich of cysteine and glycine to produce three loops that are essential for high-affinity binding to its ligand. Nearly all reported CADASIL-associated mutations result in gain or loss of a cysteine residue within the EGF-like domains. Only a few cysteine-sparing NOTCH3 mutations have been documented in the patients with CADASIL to date. Here, we reported a Chinese CADASIL family with a cysteine-sparing NOTCH3 mutation. In this family, affected patients had dizziness, memory loss, gait instability, or hemiplegia. Brain magnetic resonance imaging (MRI) showed diffuse leukoencephalopathy with confluent signal abnormalities in the periventricular white matter, basal ganglia, and centrum semiovale bilaterally. By screening the entire coding region of NOTCH3, a novel missense mutation p.G149V (c.446G>T) was found. This mutation was not detected in 400 normal controls. Considering the critical position of glycine within the C-loop of EGF-like domain and its high conservation through evolution, p.G149V mutation could be a potential pathogenic cause for CADASIL.

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

“…All the mutations, with the exception of p.R75Q, p.R75P and p.T1098S, lead to an odd number of conserved cysteine residues in the EGF-like domain. It has already been reported that NOTCH3 gene mutations not involving cysteine residues in a few cases, showing a later disease onset and a lower and milder clinical course than typical CADASIL patients with mutations involving cysteine residues [11,20]. However, those three patients with cysteine-sparing mutations exhibited similar clinical manifestations as other typical patients in our study.…”

“…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].…”

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

“…Although whether patients with several cysteine-sparing NOTCH3 mutations develop CADASIL remains to be clarified [1,10,13,[25][26][27][28][29], we clearly showed patients with this Arg75Pro mutation had deposits of the extracellular domain of Notch3 on vascular walls, which indicates that those patients are developing CADASIL. The Arg75Pro mutation was reported in Korean and Japanese CADASIL patients but was not found in Chinese and Caucasian patients [13,23].…”