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Bi-allelic loss-of-function variants in TMEM147 cause moderate to profound intellectual disability with facial dysmorphism and pseudo-Pelger-Huët anomaly.
Thomas, Quentin; Motta, Marialetizia; Gautier, Thierry; Zaki, Maha S; Ciolfi, Andrea; Paccaud, Julien; Girodon, François; Boespflug-Tanguy, Odile; Besnard, Thomas; Kerkhof, Jennifer; McConkey, Haley; Masson, Aymeric; Denommé-Pichon, Anne-Sophie; Cogné, Benjamin; Trochu, Eva; Vignard, Virginie; El It, Fatima; Rodan, Lance H; Alkhateeb, Mohammad Ayman; Jamra, Rami Abou; Duplomb, Laurence; Tisserant, Emilie; Duffourd, Yannis; Bruel, Ange-Line; Jackson, Adam; Banka, Siddharth; McEntagart, Meriel; Saggar, Anand; Gleeson, Joseph G; Sievert, David; Bae, Hyunwoo; Lee, Beom Hee; Kwon, Kisang; Seo, Go Hun; Lee, Hane; Saeed, Anjum; Anjum, Nadeem; Cheema, Huma; Alawbathani, Salem; Khan, Imran; Pinto-Basto, Jorge; Teoh, Joyce; Wong, Jasmine; Sahari, Umar Bin Mohamad; Houlden, Henry; Zhelcheska, Kristina; Pannetier, Melanie; Awad, Mona A; Lesieur-Sebellin, Marion; Barcia, Giulia.
Afiliación
  • Thomas Q; UMR1231 GAD, Inserm, Université Bourgogne-Franche Comté, Dijon, France. Electronic address: quentin.thomas@chu-dijon.fr.
  • Motta M; Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.
  • Gautier T; University Grenoble Alpes, Inserm, CNRS, Institute for Advanced Biosciences, 38000 Grenoble, France.
  • Zaki MS; Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt; Armed Forces College of Medicine, Cairo, Egypt.
  • Ciolfi A; Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.
  • Paccaud J; UMR1231 GAD, Inserm, Université Bourgogne-Franche Comté, Dijon, France.
  • Girodon F; UMR1231 GAD, Inserm, Université Bourgogne-Franche Comté, Dijon, France; Biology Division, Department of Biological Hematology, Dijon Hospital, 21000 Dijon, France.
  • Boespflug-Tanguy O; Université Paris Cité, UMR 1141 NeuroDiderot, Inserm, 75019 Paris, France; Service de Neuropédiatrie, reference center for leukodystrophies, APHP, Hopital Robert Debré, 75019 Paris, France.
  • Besnard T; Service de Génétique Médicale, CHU Nantes, Nantes, France; Université de Nantes, CHU Nantes, CNRS, Inserm, l'Institut du Thorax, 44000 Nantes, France.
  • Kerkhof J; Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON N6A 5W9, Canada.
  • McConkey H; Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON N6A 5W9, Canada; Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada.
  • Masson A; UMR1231 GAD, Inserm, Université Bourgogne-Franche Comté, Dijon, France.
  • Denommé-Pichon AS; UMR1231 GAD, Inserm, Université Bourgogne-Franche Comté, Dijon, France; Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France.
  • Cogné B; Service de Génétique Médicale, CHU Nantes, Nantes, France; Université de Nantes, CHU Nantes, CNRS, Inserm, l'Institut du Thorax, 44000 Nantes, France.
  • Trochu E; Service de Génétique Médicale, CHU Nantes, Nantes, France.
  • Vignard V; Université de Nantes, CHU Nantes, CNRS, Inserm, l'Institut du Thorax, 44000 Nantes, France.
  • El It F; UMR1231 GAD, Inserm, Université Bourgogne-Franche Comté, Dijon, France.
  • Rodan LH; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Alkhateeb MA; Women Wellness and Research Center Hamad Medical Corporation, Doha, Qatar.
  • Jamra RA; Institute of Human Genetics, University Medical Center, Leipzig, Germany.
  • Duplomb L; UMR1231 GAD, Inserm, Université Bourgogne-Franche Comté, Dijon, France.
  • Tisserant E; UMR1231 GAD, Inserm, Université Bourgogne-Franche Comté, Dijon, France.
  • Duffourd Y; UMR1231 GAD, Inserm, Université Bourgogne-Franche Comté, Dijon, France.
  • Bruel AL; UMR1231 GAD, Inserm, Université Bourgogne-Franche Comté, Dijon, France; Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France.
  • Jackson A; Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK; Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manch
  • Banka S; Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK; Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manch
  • McEntagart M; Medical Genetics, St George's University Hospitals NHS FT, London SW17 0RE, UK.
  • Saggar A; Medical Genetics, St George's University Hospitals NHS FT, London SW17 0RE, UK; The Portland Hospital, 205-209 Great Portland St, London W1W 5AH, UK.
  • Gleeson JG; Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children's Institute for Genomic Medicine, San Diego, La Jolla, CA 92093, USA.
  • Sievert D; Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
  • Bae H; Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea.
  • Lee BH; Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea.
  • Kwon K; 3billion, Inc, Seoul, South Korea.
  • Seo GH; 3billion, Inc, Seoul, South Korea.
  • Lee H; 3billion, Inc, Seoul, South Korea.
  • Saeed A; Children's Hospital and University of Child Health Lahore, Lahore, Pakistan.
  • Anjum N; Children's Hospital and University of Child Health Lahore, Lahore, Pakistan.
  • Cheema H; Children's Hospital and University of Child Health Lahore, Lahore, Pakistan.
  • Alawbathani S; CENTOGENE GmbH, 18055 Rostock, Germany.
  • Khan I; CENTOGENE GmbH, 18055 Rostock, Germany.
  • Pinto-Basto J; CENTOGENE GmbH, 18055 Rostock, Germany.
  • Teoh J; Laboratory of Human Genetics & Therapeutics, Genome Institute of Singapore, A(∗)STAR, Singapore, Singapore.
  • Wong J; Laboratory of Human Genetics & Therapeutics, Genome Institute of Singapore, A(∗)STAR, Singapore, Singapore.
  • Sahari UBM; Laboratory of Human Genetics & Therapeutics, Genome Institute of Singapore, A(∗)STAR, Singapore, Singapore.
  • Houlden H; Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK.
  • Zhelcheska K; Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK.
  • Pannetier M; Service d'Hématologie cellulaire et hémostase bioclinique, CHU Rennes, Rennes, France.
  • Awad MA; Clinical and Chemical Pathology Department, Medical Research and Clinical Studies Institute National Research Centre, Cairo, Egypt.
  • Lesieur-Sebellin M; Service de Médecine Génomique des Maladies Rares, Hôpital Necker-Enfant Malades, AP-HP, Paris, France.
  • Barcia G; Service de Médecine Génomique des Maladies Rares, Hôpital Necker-Enfant Malades, AP-HP, Paris, France.
Am J Hum Genet ; 109(10): 1909-1922, 2022 10 06.
Article en En | MEDLINE | ID: mdl-36044892
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Anomalía de Pelger-Huët / Discapacidad Intelectual / Anomalías Musculoesqueléticas Tipo de estudio: Prognostic_studies Límite: Child / Humans Idioma: En Revista: Am J Hum Genet Año: 2022 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Anomalía de Pelger-Huët / Discapacidad Intelectual / Anomalías Musculoesqueléticas Tipo de estudio: Prognostic_studies Límite: Child / Humans Idioma: En Revista: Am J Hum Genet Año: 2022 Tipo del documento: Article Pais de publicación: Estados Unidos