Disrupted SOX10 regulation of GJC2 transcription causes Pelizaeus-Merzbacher-like disease.
Mutations in the gap junction protein gamma-2 gene, GJC2, cause a central hypomyelinating disorder; Pelizaeus-Merzbacher-like disease (PMLD; MIM311601). Using a homozygosity mapping and positional candidate gene approach, we identified a homozygous mutation (c.-167A>G) within the GJC2 promoter at a potent SOX10 binding site in a patient with mild PMLD. Functionally, this mutation completely abolished the SOX10 binding and attenuated GJC2 promoter activity. These findings suggest not only that the SOX10-to-GJC2 transcriptional dysregulation is a cause of PMLD, but also that GJC2 may be in part responsible for the central hypomyelination caused by SOX10 mutations.
Osaka
Hitoshi
H
Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama, Japan. hosaka@kcmc.jp
Hamanoue
Haruka
H
Yamamoto
Ryoko
R
Nezu
Atsuo
A
Sasaki
Megumi
M
Saitsu
Hirotomo
H
Kurosawa
Kenji
K
Shimbo
Hiroko
H
Matsumoto
Naomichi
N
Inoue
Ken
K
D000328:Adult; D017630:Connexins / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D006801:Humans; D009154:Mutation; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism; D020371:Pelizaeus-Merzbacher Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D050436:Regulatory Elements, Transcriptional / Q000235:genetics; D055757:SOXE Transcription Factors / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000235:genetics
D017630:Connexins; C527923:SOX10 protein, human; D055757:SOXE Transcription Factors; C427305:connexin 47