1. Bi-allelic loss-of-function variants in TMEM147 cause moderate to profound intellectual disability with facial dysmorphism and pseudo-Pelger-Huët anomaly
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Quentin Thomas, Marialetizia Motta, Thierry Gautier, Maha S. Zaki, Andrea Ciolfi, Julien Paccaud, François Girodon, Odile Boespflug-Tanguy, Thomas Besnard, Jennifer Kerkhof, Haley McConkey, Aymeric Masson, Anne-Sophie Denommé-Pichon, Benjamin Cogné, Eva Trochu, Virginie Vignard, Fatima El It, Lance H. Rodan, Mohammad Ayman Alkhateeb, Rami Abou Jamra, Laurence Duplomb, Emilie Tisserant, Yannis Duffourd, Ange-Line Bruel, Adam Jackson, Siddharth Banka, Meriel McEntagart, Anand Saggar, Joseph G. Gleeson, David Sievert, Hyunwoo Bae, Beom Hee Lee, Kisang Kwon, Go Hun Seo, Hane Lee, Anjum Saeed, Nadeem Anjum, Huma Cheema, Salem Alawbathani, Imran Khan, Jorge Pinto-Basto, Joyce Teoh, Jasmine Wong, Umar Bin Mohamad Sahari, Henry Houlden, Kristina Zhelcheska, Melanie Pannetier, Mona A. Awad, Marion Lesieur-Sebellin, Giulia Barcia, Jeanne Amiel, Julian Delanne, Christophe Philippe, Laurence Faivre, Sylvie Odent, Aida Bertoli-Avella, Christel Thauvin, Bekim Sadikovic, Bruno Reversade, Reza Maroofian, Jérôme Govin, Marco Tartaglia, Antonio Vitobello, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), CHU Pontchaillou [Rennes], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de référence Maladies Rares CLAD-Ouest [Rennes], FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), and This work was supported by grants from Dijon University Hospital, the ISITE-BFC (PIA ANR), and the European Union through the FEDER programs, EJP-RD (NSEuroNET), AIRC (IG21614), and Italian Ministry of Health (5x1000). Sequencing for individual 15 was funded by the Institute for Information and Communications Technology Promotion (IITP) grant from the Korean government (MSIT) (2018-0-00861, Intelligent SW Technology Development for Medical Data Analysis). This study makes use of DECIPHER (http://decipher.sanger.ac.uk), which is funded by the Wellcome (www.ddduk.org/access.html).55 This research was made possible through access to the data and findings generated by the 100KGP. The 100KGP is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100KGP is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK, and the Medical Research Council have also funded research infrastructure. The 100KGP uses data provided by individuals and collected by the National Health Service as part of their care and support. Several authors of this publication are members of the European Reference Network for Developmental Anomalies and Intellectual Disability (ERN-ITHACA). The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement no. 779257.
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Cell Nucleus ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,DNA methylation ,Loss of Heterozygosity ,facial dysmorphism ,neurodevelopmental disorder ,Chromatin ,Musculoskeletal Abnormalities ,transcriptomics ,translocon dysfunction ,Pelger-Huët anomaly ,intellectual disability ,Genetics ,LBR ,Humans ,TMEM147 ,nuclear envelope instability ,Child ,Pelger-Huet Anomaly ,Genetics (clinical) - Abstract
International audience; The transmembrane protein TMEM147 has a dual function: first at the nuclear envelope, where it anchors lamin B receptor (LBR) to the inner membrane, and second at the endoplasmic reticulum (ER), where it facilitates the translation of nascent polypeptides within the ribosome-bound TMCO1 translocon complex. Through international data sharing, we identified 23 individuals from 15 unrelated families with bi-allelic TMEM147 loss-of-function variants, including splice-site, nonsense, frameshift, and missense variants. These affected children displayed congruent clinical features including coarse facies, developmental delay, intellectual disability, and behavioral problems. In silico structural analyses predicted disruptive consequences of the identified amino acid substitutions on translocon complex assembly and/or function, and in vitro analyses documented accelerated protein degradation via the autophagy-lysosomal-mediated pathway. Furthermore, TMEM147-deficient cells showed CKAP4 (CLIMP-63) and RTN4 (NOGO) upregulation with a concomitant reorientation of the ER, which was also witnessed in primary fibroblast cell culture. LBR mislocalization and nuclear segmentation was observed in primary fibroblast cells. Abnormal nuclear segmentation and chromatin compaction were also observed in approximately 20% of neutrophils, indicating the presence of a pseudo-Pelger-Huët anomaly. Finally, co-expression analysis revealed significant correlation with neurodevelopmental genes in the brain, further supporting a role of TMEM147 in neurodevelopment. Our findings provide clinical, genetic, and functional evidence that bi-allelic loss-of-function variants in TMEM147 cause syndromic intellectual disability due to ER-translocon and nuclear organization dysfunction.
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