Functional validation of novel MKS3/TMEM67 mutations in COACH syndrome

被引：11

作者：

Lee, So-Hyun ^{[1
,2
]}

Nam, Tai-Seung ^{[3
]}

Li, Wenting ^{[1
]}

Kim, Jung Ha ^{[4
]}

Yoon, Woong ^{[5
]}

Choi, Yoo-Duk ^{[6
]}

Kim, Kun-Hee ^{[7
]}

Cai, Hua ^{[1
]}

Kim, Min Jung ^{[8
]}

Kim, Changsoo ^{[9
]}

Choy, Hyon E. ^{[7
]}

Kim, Nacksung ^{[4
]}

Chay, Kee Oh ^{[10
]}

Kim, Myeong-Kyu ^{[3
]}

Choi, Seok-Yong ^{[1
]}

机构：

[1] Chonnam Natl Univ, Med Sch, Dept Biomed Sci, Gwangju, South Korea

[2] Chonnam Natl Univ, Ctr Creat Biomed Scientists, Gwangju, South Korea

[3] Chonnam Natl Univ, Med Sch, Dept Neurol, Gwangju, South Korea

[4] Chonnam Natl Univ, Med Sch, Dept Pharmacol, Gwangju, South Korea

[5] Chonnam Natl Univ, Med Sch, Dept Radiol, Gwangju, South Korea

[6] Chonnam Natl Univ, Med Sch, Dept Pathol, Gwangju, South Korea

[7] Chonnam Natl Univ, Med Sch, Dept Microbiol, Gwangju, South Korea

[8] Sookmyung Womens Univ, Dept Biol Sci, Seoul, South Korea

[9] Chonnam Natl Univ, Sch Biol Sci & Technol, Gwangju, South Korea

[10] Chonnam Natl Univ, Med Sch, Dept Biochem, Gwangju, South Korea

来源：

SCIENTIFIC REPORTS | 2017年 / 7卷

基金：

新加坡国家研究基金会;

关键词：

MECKEL-GRUBER-SYNDROME; JOUBERT-SYNDROME; PRIMARY CILIUM; MECHANISMS; HEDGEHOG; CILIOGENESIS; PLEIOTROPY; GENETICS; DISEASE; TMEM67;

D O I：

10.1038/s41598-017-10652-z

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.-glutamyl transpeptidase (gamma-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.

引用

页数：9