Missense Variants in the Second Transmembrane Domain of TMEM17 Disrupt Its Stability and Function and Lead to a Wide Phenotypic Spectrum of Ciliopathies.

IF 2.3 3区 医学 Q2 GENETICS & HEREDITY
Lucile Boutaud, Chunmei Li, Candice Moncler, Laure Verlin, Meriem Garfa-Traoré, Nicolas Bourgon, Dhruvin Akbari, Jeanne Porée, Valentina Serpieri, Marine Panza, Lynda Haddad, Patrick Nitschké, Jacqueline Aziza, Cristina Matt, Enza Maria Valente, Patricia Gargallo, Charlotte Dubucs, Tania Attié-Bitach, Michel R Leroux, Sophie Thomas
{"title":"Missense Variants in the Second Transmembrane Domain of TMEM17 Disrupt Its Stability and Function and Lead to a Wide Phenotypic Spectrum of Ciliopathies.","authors":"Lucile Boutaud, Chunmei Li, Candice Moncler, Laure Verlin, Meriem Garfa-Traoré, Nicolas Bourgon, Dhruvin Akbari, Jeanne Porée, Valentina Serpieri, Marine Panza, Lynda Haddad, Patrick Nitschké, Jacqueline Aziza, Cristina Matt, Enza Maria Valente, Patricia Gargallo, Charlotte Dubucs, Tania Attié-Bitach, Michel R Leroux, Sophie Thomas","doi":"10.1111/cge.70042","DOIUrl":null,"url":null,"abstract":"<p><p>Ciliopathies are rare genetic disorders characterized by significant genetic and phenotypic variability. Over 140 proteins localized to primary cilia, which are sensory organelles essential for vertebrate development, are implicated. TMEM17 encodes a transmembrane protein at the ciliary transition zone and was previously proposed as a potential ciliopathy gene, based on reports of individuals from two families with orofaciodigital syndrome type 6 (OFD6) and Joubert syndrome (JS). Here, we report two unrelated fetuses with occipital encephalocele, polydactyly, and kidney cysts, in whom exome sequencing identified a founder homozygous missense variant (Arg94Trp) in TMEM17, affecting a highly conserved residue. This expands the TMEM17-associated phenotypic spectrum to include Meckel syndrome (MKS). Comprehensive functional analyses of all known TMEM17 variants, using patient tissues/cells and a C. elegans model system, demonstrate a loss-of-function mechanism. Our study reveals severe functional consequences, including TMEM17 destabilization and mislocalization, anomalies in cilium composition and function, and abrogation of Sonic Hedgehog signaling. These experiments confirm the pathogenicity of all TMEM17 variants and underscore its essential role at the ciliary transition zone. Collectively, our findings establish TMEM17 as a bona fide ciliopathy gene, associated with a wide phenotypic spectrum ranging from viable syndromes (OFD6 and JS) to a fetal-lethal condition (MKS).</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3000,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Genetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1111/cge.70042","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
引用次数: 0

Abstract

Ciliopathies are rare genetic disorders characterized by significant genetic and phenotypic variability. Over 140 proteins localized to primary cilia, which are sensory organelles essential for vertebrate development, are implicated. TMEM17 encodes a transmembrane protein at the ciliary transition zone and was previously proposed as a potential ciliopathy gene, based on reports of individuals from two families with orofaciodigital syndrome type 6 (OFD6) and Joubert syndrome (JS). Here, we report two unrelated fetuses with occipital encephalocele, polydactyly, and kidney cysts, in whom exome sequencing identified a founder homozygous missense variant (Arg94Trp) in TMEM17, affecting a highly conserved residue. This expands the TMEM17-associated phenotypic spectrum to include Meckel syndrome (MKS). Comprehensive functional analyses of all known TMEM17 variants, using patient tissues/cells and a C. elegans model system, demonstrate a loss-of-function mechanism. Our study reveals severe functional consequences, including TMEM17 destabilization and mislocalization, anomalies in cilium composition and function, and abrogation of Sonic Hedgehog signaling. These experiments confirm the pathogenicity of all TMEM17 variants and underscore its essential role at the ciliary transition zone. Collectively, our findings establish TMEM17 as a bona fide ciliopathy gene, associated with a wide phenotypic spectrum ranging from viable syndromes (OFD6 and JS) to a fetal-lethal condition (MKS).

TMEM17第二跨膜结构域的错义变异破坏了其稳定性和功能,并导致了广泛的纤毛病表型谱。
纤毛病是一种罕见的遗传疾病,其特征是显著的遗传和表型变异。超过140个蛋白质定位于初级纤毛,这是脊椎动物发育所必需的感觉细胞器,涉及。TMEM17在纤毛过渡区编码一种跨膜蛋白,之前根据来自6型口指综合征(OFD6)和Joubert综合征(JS)两个家族的个体的报道,TMEM17被认为是潜在的纤毛病基因。在这里,我们报道了两个不相关的胎儿,他们患有枕部脑泡、多指畸形和肾囊肿,在他们的外显子组测序中发现了TMEM17中的一个创始人纯合错义变体(Arg94Trp),影响了一个高度保守的残基。这扩大了tmem17相关表型谱,包括Meckel综合征(MKS)。利用患者组织/细胞和秀丽隐杆线虫模型系统对所有已知的TMEM17变体进行综合功能分析,证明了功能丧失机制。我们的研究揭示了严重的功能后果,包括TMEM17不稳定和错误定位,纤毛组成和功能异常,以及Sonic Hedgehog信号的消失。这些实验证实了所有TMEM17变异的致病性,并强调了其在纤毛过渡区的重要作用。总的来说,我们的研究结果确定TMEM17是一个真正的纤毛病基因,与广泛的表型谱相关,从可存活综合征(OFD6和JS)到胎儿致死状况(MKS)。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Clinical Genetics
Clinical Genetics 医学-遗传学
CiteScore
6.50
自引率
0.00%
发文量
175
审稿时长
3-8 weeks
期刊介绍: Clinical Genetics links research to the clinic, translating advances in our understanding of the molecular basis of genetic disease for the practising clinical geneticist. The journal publishes high quality research papers, short reports, reviews and mini-reviews that connect medical genetics research with clinical practice. Topics of particular interest are: • Linking genetic variations to disease • Genome rearrangements and disease • Epigenetics and disease • The translation of genotype to phenotype • Genetics of complex disease • Management/intervention of genetic diseases • Novel therapies for genetic diseases • Developmental biology, as it relates to clinical genetics • Social science research on the psychological and behavioural aspects of living with or being at risk of genetic disease
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信