title: Hypomorphic NOTCH3 alleles do not cause CADASIL in humans.
abstract: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by stereotyped missense mutations in NOTCH3. 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 NOTCH3 mutations, both leading to a premature stop codon with predicted loss of NOTCH3 function. The first mutation, c.307C>T, p.Arg103*, 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 NOTCH3 mutation (c.2129A>G, p.Tyr710Cys) 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 NOTCH3 mutations indicate that hypomorphic NOTCH3 alleles do not cause CADASIL.
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands; Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Julie W
authors.initials: JW
authors.lastname: Rutten
authors.forename: Elles M J
authors.initials: EM
authors.lastname: Boon
authors.forename: Michael K
authors.initials: MK
authors.lastname: Liem
authors.forename: Johannes G
authors.initials: JG
authors.lastname: Dauwerse
authors.forename: Margot J
authors.initials: MJ
authors.lastname: Pont
authors.forename: Ellen
authors.initials: E
authors.lastname: Vollebregt
authors.forename: Anneke J
authors.initials: AJ
authors.lastname: Maat-Kievit
authors.forename: Hendrika B
authors.initials: HB
authors.lastname: Ginjaar
authors.forename: Phillis
authors.initials: P
authors.lastname: Lakeman
authors.forename: Sjoerd G
authors.initials: SG
authors.lastname: van Duinen
authors.forename: Gisela M
authors.initials: GM
authors.lastname: Terwindt
authors.forename: Saskia A J
authors.initials: SA
authors.lastname: Lesnik Oberstein
mesh_terms: D000328:Adult; D000483:Alleles; D001921:Brain / Q000473:pathology; D046589:CADASIL / Q000175:diagnosis* / Q000235:genetics*; D004252:DNA Mutational Analysis; D006579:Heterozygote; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics*; D017384:Sequence Deletion
chemical_list: C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D051880:Receptors, Notch
keywords: CADASIL; NOTCH3; deletion; hypomorphic allele; nonsense mutation