Open AccessSomatic mutations in GLI 3 and OFD 1 involved in sonic hedgehog signaling cause hypothalamic hamartoma
Author(s) -
Saitsu Hirotomo,
Sonoda Masaki,
Higashijima Takefumi,
Shirozu Hiroshi,
Masuda Hiroshi,
Tohyama Jun,
Kato Mitsuhiro,
Nakashima Mitsuko,
Tsurusaki Yoshinori,
Mizuguchi Takeshi,
Miyatake Satoko,
Miyake Noriko,
Kameyama Shigeki,
Matsumoto Naomichi
Publication year - 2016
Publication title -
annals of clinical and translational neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.824
H-Index - 42
ISSN - 2328-9503
DOI - 10.1002/acn3.300
Subject(s) - sanger sequencing , somatic cell , genetics , germline mutation , exome sequencing , biology , nonsense mutation , mutation , hedgehog , gli3 , cancer research , gene , missense mutation , repressor , transcription factor
Abstract Objective Hypothalamic hamartoma ( HH ) is a congenital anomalous brain tumor. Although most HH s are found without any other systemic features, HH is observed in syndromic disorders such as Pallister–Hall syndrome ( PHS ) and oral‐facial‐digital syndrome ( OFD ). Here, we explore the possible involvement of somatic mutations in HH . Methods We analyzed paired blood and hamartoma samples from 18 individuals, including three with digital anomalies, by whole‐exome sequencing. Detected somatic mutations were validated by Sanger sequencing and deep sequencing of target amplicons. The effect of GLI 3 mutations on its transcriptional properties was evaluated by luciferase assays using reporters containing eight copies of the GLI ‐binding site and a mutated control sequence disrupting GLI binding. Results We found hamartoma‐specific somatic truncation mutations in GLI 3 and OFD 1 , known regulators of sonic hedgehog (Shh) signaling, in two and three individuals, respectively. Deep sequencing of amplicons covering the mutations showed mutant allele rates of 7–54%. Somatic mutations in OFD 1 at Xp22 were found only in male individuals. Potential pathogenic somatic mutations in UBR 5 and ZNF 263 were also identified in each individual. Germline nonsense mutations in GLI 3 and OFD 1 were identified in each individual with PHS and OFD type I in our series, respectively. The truncated GLI 3 showed stronger repressor activity than the wild‐type protein. We did not detect somatic mutations in the remaining 9 individuals. Interpretation Our data indicate that a spectrum of human disorders can be caused by lesion‐specific somatic mutations, and suggest that impaired Shh signaling is one of the pathomechanisms of HH .