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BOC is a modifier gene in holoprosencephaly
Author(s) -
Hong Mingi,
Srivastava Kshitij,
Kim Sungjin,
Allen Benjamin L.,
Leahy Daniel J.,
Hu Ping,
Roessler Erich,
Krauss Robert S.,
Muenke Maximilian
Publication year - 2017
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.23286
Subject(s) - holoprosencephaly , sonic hedgehog , biology , genetics , missense mutation , penetrance , loss function , gene , expressivity , allele , forebrain , mutation , phenotype , endocrinology , pregnancy , fetus , central nervous system
Holoprosencephaly (HPE), a common developmental defect of the forebrain and midface, has a complex etiology. Heterozygous, loss‐of‐function mutations in the sonic hedgehog (SHH) pathway are associated with HPE. However, mutation carriers display highly variable clinical presentation, leading to an “autosomal dominant with modifier” model, in which the penetrance and expressivity of a predisposing mutation is graded by genetic or environmental modifiers. Such modifiers have not been identified. Boc encodes a SHH coreceptor and is a silent HPE modifier gene in mice. Here, we report the identification of missense BOC variants in HPE patients. Consistent with these alleles functioning as HPE modifiers, individual variant BOC proteins had either loss‐ or gain‐of‐function properties in cell‐based SHH signaling assays. Therefore, in addition to heterozygous loss‐of‐function mutations in specific SHH pathway genes and an ill‐defined environmental component, our findings identify a third variable in HPE: low‐frequency modifier genes, BOC being the first identified.