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Hypomorphic NOTCH 3 Alleles Do Not Cause CADASIL in Humans
Author(s) -
Rutten Julie W.,
Boon Elles M.J.,
Liem Michael K.,
Dauwerse Johannes G.,
Pont Margot J.,
Vollebregt Ellen,
MaatKievit Anneke J.,
Ginjaar Hendrika B.,
Lakeman Phillis,
Duinen Sjoerd G.,
Terwindt Gisela M.,
Lesnik Oberstein Saskia A.J.
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22432
Subject(s) - cadasil , leukoencephalopathy , frameshift mutation , missense mutation , biology , genetics , allele , mutation , phenotype , skin biopsy , pathology , gene , biopsy , medicine , disease
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy ( CADASIL ) is caused by stereotyped missense mutations in NOTCH 3 . Whether these mutations lead to the CADASIL phenotype via a neomorphic effect, or rather by a hypomorphic effect, is subject of debate. Here, we report two novel NOTCH 3 mutations, both leading to a premature stop codon with predicted loss of NOTCH 3 function. The first mutation, c.307 C > T , p. A rg103*, was detected in two brothers aged 50 and 55 years, with a brain MRI and skin biopsy incompatible with CADASIL . The other mutation was found in a 40‐year‐old CADASIL patient compound heterozygous for a pathogenic NOTCH 3 mutation (c.2129 A > G , p. T yr710 C ys) and an intragenic frameshift deletion. The deletion was inherited from his father, who did not have the skin biopsy abnormalities seen in CADASIL patients. These individuals with rare NOTCH 3 mutations indicate that hypomorphic NOTCH 3 alleles do not cause CADASIL .