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

Sep 30, 2026

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Ciliopathies are rare genetic disorders with pronounced genetic and phenotypic variability driven by dysfunction of primary cilia, sensory organelles required for vertebrate development. TMEM17 encodes a ciliary transition zone transmembrane protein previously suggested as a ciliopathy gene. Exome sequencing in two unrelated fetuses identified a homozygous founder missense variant, Arg94Trp, associated with occipital encephalocele, polydactyly, and kidney cysts. Functional studies of TMEM17 variants show a loss-of-function mechanism causing TMEM17 destabilization and mislocalization, cilium composition and functional defects, and loss of Sonic Hedgehog signaling, expanding the TMEM17 spectrum to include Meckel syndrome.

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Introduction

Cilia and primary cilia functions

Ciliopathies and phenotypic variability

Clinical Genetics ORIGINAL ARTICLE OPEN ACCESS Missense Variants in the Second Transmembrane Domain ofTMEM17 Disrupt Its Stability and Function and Lead toa Wide Phenotypic Spectrum ofCiliopathies Lucile Boutaud1,2 | Chunmei Li3,4 | Candice Moncler1 | Laure Verlin1 | Meriem Garfa-Traoré5 | Nicolas Bourgon2 | Dhruvin Akbari3,4 | Jeanne Porée1,5 | Valentina Serpieri6 | Marine Panza5 | Lynda Haddad2 | Patrick Nitschké7 | Jacqueline Aziza8 | Cristina Matt9 | Enza Maria Valente6,10 | Patricia Gargallo9 | Charlotte Dubucs8 | Tania Attié-Bitach1,2 | Michel R. Leroux3,4 | Sophie Thomas1 1INSERM UMR 1163, Institut Imagine, Université Paris Cité, Paris, France | 2Service de Médecine Génomique des Maladies Rares, Hôpital Universitaire Necker-Enfants Malades, Paris, France | 3Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada | 4Centre for Cell Biology, Development, and Disease, Simon Fraser University, Burnaby, British Columbia, Canada | 5Cell Imaging Platform, INSERM-US24-CNRS UMS 3633 Structure Fédérative de Recherche Necker, Paris University, Paris, France | 6Department of Molecular Medicine, University of Pavia, Pavia, Italy | 7Imagine Institute, Bioinformatics Platform, INSERM UMR 1163, Université de Paris, Paris, France | 8Département de Pathologie, Institut Universitaire du Cancer Toulouse – Oncopole, Toulouse, France | 9Seccion de Genética Médica del Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno”, CP (C1431FWO), Buenos Aires, Argentina | 10Neurogenetics Research Center, IRCCS, Mondino Foundation, Pavia, Italy Correspondence: Tania Attié-Bitach ([tania.attie@inserm.fr](tania.attie@inserm.fr)) | Michel R. Leroux ([leroux@sfu.ca](leroux@sfu.ca)) | Sophie Thomas ([sophie.thomas@inserm.fr](sophie.thomas@inserm.fr)) Received: 28 May 2025 | Revised: 28 July 2025 | Accepted: 1 August 2025 Funding: This work was supported by Canadian Institutes of Health Research (MOP-142243, PJT-156042), Telethon Foundation Italy (GGP20070), Agence Nationale de la Recherche (ANR-17-CE16-0003-01, ANR-17-RHUS-0002; ANR-10-IAHU-01) and Michael Smith Foundation for Health Research. Keywords: ciliopathy | Joubert syndrome | Meckel syndrome | Oro-Facio-digital syndrome | primary cilium | TMEM17 | transition zone 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 encodesa 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) . | Lucile Boutaud, Chunmei Li and Candice Moncler contributed equally to this work. | | --- | | This is an open access article under the terms of the Creative Commo

FAQs

What did the exome sequencing identify in the two unrelated fetuses?

It identified a homozygous founder missense variant (Arg94Trp) in TMEM17. The variant affects a highly conserved residue and was present in fetuses with occipital encephalocele, polydactyly, and kidney cysts.

How do TMEM17 variants affect cellular function according to the study?

Comprehensive functional analyses indicate a loss-of-function mechanism. TMEM17 destabilization and mislocalization lead to ciliary composition and function defects and abrogation of Sonic Hedgehog signaling.

What phenotypic conditions does the study link to TMEM17?

The TMEM17-associated phenotypic spectrum includes Joubert syndrome and orofacio-digital syndrome in viable syndromes and expands to include Meckel syndrome as a fetal-lethal condition.

Sep 30, 2026

Uploaded by Grenda