RRC ID 51254
Author Lee SH, Nam TS, Li W, Kim JH, Yoon W, Choi YD, Kim KH, Cai H, Kim MJ, Kim C, Choy HE, Kim N, Chay KO, Kim MK, Choi SY.
Title Functional validation of novel MKS3/TMEM67 mutations in COACH syndrome.
Journal Sci Rep
Abstract COACH syndrome is an autosomal recessive developmental disorder, a subtype of Joubert syndrome and related disorders, characterized by cerebellar vermis hypoplasia, oligophrenia, ataxia, coloboma, and hepatic fibrosis. Although mutations in TMEM67 (transmembrane protein 67)/MKS3 (Meckel-Gruber syndrome, type 3) were reported to cause COACH syndrome, this causality has not verified by functional studies. In a 20-year-old Korean man, we found cerebellar ataxia, isolated elevation in serum γ-glutamyl transpeptidase (γ-GTP) activity, oligophrenia, the molar tooth sign (MTS) in the brain MR images and congenital hepatic fibrosis (CHF). Two novel compound heterozygous mutations were found in TMEM67 in the patient: i) missense mutation (c.395 G > C and p.Gly132Ala) in exon 3, and ii) deletion in exon 26 (c.2758delT and p.Tyr920ThrfsX40). Western blotting showed that the p.Tyr920ThrfsX40 mutation accelerates turnover of the TMEM67 protein. Although wild-type human TMEM67 RNA rescued phenotypes of zebrafish embryos injected with anti-sense oligonucleotide morpholinos against tmem67, the two human TMEM67 RNAs individually harboring the two mutations did not. Finally, Wnt signaling, but not Hedgehog signaling, was suppressed in tmem67 morphants. To the best of our knowledge, this is the first report verifying the causality between COACH syndrome and TMEM67, which will further our understanding of molecular pathogenesis of the syndrome.
Volume 7(1)
Pages 10222
Published 2017-8-31
DOI 10.1038/s41598-017-10652-z
PII 10.1038/s41598-017-10652-z
PMID 28860541
PMC PMC5579020
MeSH Abnormalities, Multiple / drug therapy Abnormalities, Multiple / genetics* Abnormalities, Multiple / metabolism Animals Ataxia / drug therapy Ataxia / genetics* Ataxia / metabolism Brain / abnormalities* Brain / metabolism Cholestasis / drug therapy Cholestasis / genetics* Cholestasis / metabolism Coloboma / drug therapy Coloboma / genetics* Coloboma / metabolism Disease Models, Animal HEK293 Cells Humans Liver Diseases / drug therapy Liver Diseases / genetics* Liver Diseases / metabolism Male Membrane Proteins / genetics* Membrane Proteins / metabolism* Morpholinos / administration & dosage Morpholinos / pharmacology Mutation* Mutation, Missense Sequence Deletion Wnt Signaling Pathway Young Adult Zebrafish
IF 3.998
Times Cited 1
Zebrafish Tg(6xTcf/LefBS-miniP:d2EGFP)