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An Impairment of Long Distance SOX 10 Regulatory Elements Underlies Isolated H irschsprung Disease
Author(s) -
Lecerf Laure,
Kavo Anthula,
RuizFerrer Macarena,
Baral Viviane,
Watanabe Yuli,
Chaoui Asma,
Pingault Veronique,
Borrego Salud,
Bondurand Nadege
Publication year - 2014
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.22499
Subject(s) - sox10 , enhancer , biology , genetics , neural crest , point mutation , mutation , transcription factor , gene
A deletion encompassing several SOX 10 enhancers was recently identified in a patient presenting with W aardenburg syndrome type 4 ( WS 4), which is defined as a combination of H irschsprung disease ( HSCR , intestinal aganglionosis) and WS (deafness and pigmentation defects). The expression patterns of some of the known SOX 10 enhancers in animal models led to the speculation that endophenotypes of WS 4 may be linked to mutations within some of these sequences. The present study investigated deletions and point mutations within four SOX 10 enhancers in 144 unexplained isolated HSCR cases. One deletion and two point mutations affecting binding sites for known neural crest transcription factors were identified. In vitro functional analysis revealed that the first point mutation disrupts autoregulation by SOX 10, whereas the second affects AP 2a and SOX 10 synergistic activity. The present findings suggest that the mutations within SOX 10 enhancers contribute to isolated HSCR .