TY - JOUR
T1 - Hypomorphic NOTCH3 Alleles Do Not Cause CADASIL in Humans
AU - Rutten, Julie W.
AU - Boon, Elles M. J.
AU - Liem, Michael K.
AU - Dauwerse, Johannes G.
AU - Pont, Margot J.
AU - Vollebregt, Ellen
AU - Maat-Kievit, Anneke J.
AU - Ginjaar, Hendrika B.
AU - Lakeman, Phillis
AU - van Duinen, Sjoerd G.
AU - Terwindt, Gisela M.
AU - Lesnik Oberstein, Saskia A. J.
PY - 2013
Y1 - 2013
N2 - 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
AB - 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
U2 - https://doi.org/10.1002/humu.22432
DO - https://doi.org/10.1002/humu.22432
M3 - Article
C2 - 24000151
SN - 1059-7794
VL - 34
SP - 1486
EP - 1489
JO - Human mutation
JF - Human mutation
IS - 11
ER -