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Archetypal NOTCH3 mutations frequent in public exome: implications for CADASIL.

ABSTRACT: To determine the frequency of distinctive EGFr cysteine altering NOTCH3 mutations in the 60,706 exomes of the exome aggregation consortium (ExAC) database.ExAC was queried for mutations distinctive for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), namely mutations leading to a cysteine amino acid change in one of the 34 EGFr domains of NOTCH3. The genotype-phenotype correlation predicted by the ExAC data was tested in an independent cohort of Dutch CADASIL patients using quantified MRI lesions. The Dutch CADASIL registry was probed for paucisymptomatic individuals older than 70 years.We identified 206 EGFr cysteine altering NOTCH3 mutations in ExAC, with a total prevalence of 3.4/1000. More than half of the distinct mutations have been previously reported in CADASIL patients. Despite the clear overlap, the mutation distribution in ExAC differs from that in reported CADASIL patients, as mutations in ExAC are predominantly located outside of EGFr domains 1-6. In an independent Dutch CADASIL cohort, we found that patients with a mutation in EGFr domains 7-34 have a significantly lower MRI lesion load than patients with a mutation in EGFr domains 1-6.The frequency of EGFr cysteine altering NOTCH3 mutations is 100-fold higher than expected based on estimates of CADASIL prevalence. This challenges the current CADASIL disease paradigm, and suggests that certain mutations may more frequently cause a much milder phenotype, which may even go clinically unrecognized. Our data suggest that individuals with a mutation located in EGFr domains 1-6 are predisposed to the more severe "classical" CADASIL phenotype, whereas individuals with a mutation outside of EGFr domains 1-6 can remain paucisymptomatic well into their eighth decade.

SUBMITTER: Rutten JW

PROVIDER: S-EPMC5099530 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Archetypal <i>NOTCH3</i> mutations frequent in public exome: implications for CADASIL.

Rutten Julie W JW Dauwerse Hans G HG Gravesteijn Gido G van Belzen Martine J MJ van der Grond Jeroen J Polke James M JM Bernal-Quiros Manuel M Lesnik Oberstein Saskia A J SA

Annals of clinical and translational neurology 20160928 11

<h4>Objective</h4>To determine the frequency of distinctive EGFr cysteine altering <i>NOTCH3</i> mutations in the 60,706 exomes of the exome aggregation consortium (ExAC) database.<h4>Methods</h4>ExAC was queried for mutations distinctive for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), namely mutations leading to a cysteine amino acid change in one of the 34 EGFr domains of NOTCH3. The genotype-phenotype correlation predicted by the ExAC ...[more]

PMID: 27844030

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Project description:Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary subcortical vascular dementia. It is caused by mutations in NOTCH3 gene, which encodes a large transmembrane receptor Notch3. The key pathological finding is the accumulation of granular osmiophilic material (GOM), which contains extracellular domains of Notch3, on degenerating vascular smooth muscle cells (VSMCs). GOM has been considered specifically diagnostic for CADASIL, but the reports on the sensitivity of detecting GOM in patients' skin biopsy have been contradictory. To solve this contradiction, we performed a retrospective investigation of 131 Finnish, Swedish and French CADASIL patients, who had been adequately examined for both NOTCH3 mutation and presence of GOM. The patients were examined according to the diagnostic practice in each country. NOTCH3 mutations were assessed by restriction enzyme analysis of specific mutations or by sequence analysis. Presence of GOM was examined by electron microscopy (EM) in skin biopsies. Biopsies of 26 mutation-negative relatives from CADASIL families served as the controls. GOM was detected in all 131 mutation positive patients. Altogether our patients had 34 different pathogenic mutations which included three novel point mutations (p.Cys67Ser, p.Cys251Tyr and p.Tyr1069Cys) and a novel duplication (p.Glu434_Leu436dup). The detection of GOM by EM in skin biopsies was a highly reliable diagnostic method: in this cohort the congruence between NOTCH3 mutations and presence of GOM was 100%. However, due to the retrospective nature of this study, exact figure for sensitivity cannot be determined, but it would require a prospective study to exclude possible selection bias. The identification of a pathogenic NOTCH3 mutation is an indisputable evidence for CADASIL, but demonstration of GOM provides a cost-effective guide for estimating how far one should proceed with the extensive search for a new or an uncommon mutations among the presently known over 170 different NOTCH3 gene defects. The diagnostic skin biopsy should include the border zone between deep dermis and upper subcutis, where small arterial vessels of correct size are located. Detection of GOM requires technically adequate biopsies and distinction of true GOM from fallacious deposits. If GOM is not found in the first vessel or biopsy, other vessels or additional biopsies should be examined.

Project description:Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominant small-vessel disease of the brain caused by mutations in the NOTCH3 receptor. The highly stereotyped nature of the mutations, which alter the number of cysteine residues within the epidermal growth factor-like repeats (EGFR), predicts that all mutations share common mechanisms. Prior in vitro assays and genetic studies in the mouse support the hypothesis that common mutations do not compromise canonical Notch3 function but instead convey a non-physiological and deleterious activity to the receptor through the unpaired cysteine residue. Intriguingly, in vitro studies predict that mutations located in the Delta/Serrate/LAG-2 ligand binding domain-(EGFR10-11) may result in a loss of Notch3 receptor function. However, the in vivo relevance and functional significance of this with respect to the pathogenic mechanisms and clinical expression of the disease remain largely unexplored. To ascertain, in vivo, the functional significance of EGFR10-11 mutations, we generated transgenic mice with one representative mutation (C428S) in EGFR10 of Notch3. These mice, like those with a common R90C mutation, developed characteristic arterial accumulation of Notch3 protein and granular osmiophilic material upon aging. By introducing the mutant C428S transgene into a Notch3 null background, we found that, unlike the R90C mutant protein, the C428S mutant protein has lost wild-type Notch3 activity and exhibited mild dominant-negative activity in three different biological settings. From a large prospectively recruited cohort of 176 CADASIL patients, we identified 10 patients, from five distinct pedigrees carrying a mutation in EGFR10 or 11. These mutations were associated with significantly higher Mini-Mental State Examination and Mattis Dementia Rating Scale scores (P < 0.05), when compared with common mutations. Additionally, we found a strong effect of this genotype on the burden of white matter hyperintensities (P < 0.01). Collectively, these results highlight distinctive functional and phenotypic features of EGFR10-11 mutations relative to the common CADASIL mutations. Our findings are compatible with the hypothesis that EGFR10-11 mutations cause the disease through the same gain of novel function as the common mutations, and lead us to propose that reduced Notch3 signalling acts as a modifier of the CADASIL phenotype.

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Archetypal NOTCH3 mutations frequent in public exome: implications for CADASIL.

Publications

Archetypal <i>NOTCH3</i> mutations frequent in public exome: implications for CADASIL.

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