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Variants in the WDR44 WD40-repeat domain cause a spectrum of ciliopathy by impairing ciliogenesis initiation.
Accogli, Andrea; Shakya, Saurabh; Yang, Taewoo; Insinna, Christine; Kim, Soo Yeon; Bell, David; Butov, Kirill R; Severino, Mariasavina; Niceta, Marcello; Scala, Marcello; Lee, Hyun Sik; Yoo, Taekyeong; Stauffer, Jimmy; Zhao, Huijie; Fiorillo, Chiara; Pedemonte, Marina; Diana, Maria C; Baldassari, Simona; Zakharova, Viktoria; Shcherbina, Anna; Rodina, Yulia; Fagerberg, Christina; Roos, Laura Sønderberg; Wierzba, Jolanta; Dobosz, Artur; Gerard, Amanda; Potocki, Lorraine; Rosenfeld, Jill A; Lalani, Seema R; Scott, Tiana M; Scott, Daryl; Azamian, Mahshid S; Louie, Raymond; Moore, Hannah W; Champaigne, Neena L; Hollingsworth, Grace; Torella, Annalaura; Nigro, Vincenzo; Ploski, Rafal; Salpietro, Vincenzo; Zara, Federico; Pizzi, Simone; Chillemi, Giovanni; Ognibene, Marzia; Cooney, Erin; Do, Jenny; Linnemann, Anders; Larsen, Martin J; Specht, Suzanne; Walters, Kylie J.
Afiliación
  • Accogli A; Division of Medical Genetics, Department of Specialized Medicine, McGill University Health Centre (MUHC), Montreal, QC, Canada.
  • Shakya S; Department of Human Genetics, McGill University, Montreal, QC, Canada.
  • Yang T; Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
  • Insinna C; Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, 08826, Seoul, Republic of Korea.
  • Kim SY; Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
  • Bell D; Department of Genomic Medicine, Seoul National University Hospital, 03080, Seoul, Republic of Korea.
  • Butov KR; Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
  • Severino M; Department of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, 117997, Russia.
  • Niceta M; Department of Molecular Biology and Medical Biotechnology, Pirogov Russian National Research Medical University, Moscow, 117997, Russia.
  • Scala M; Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
  • Lee HS; Molecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146, Rome, Italy.
  • Yoo T; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Università Degli Studi di Genova, Genoa, Italy.
  • Stauffer J; Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
  • Zhao H; School of Biological Sciences, Seoul National University, 08826, Seoul, Republic of Korea.
  • Fiorillo C; Department of Biomedical Sciences, Seoul National University College of Medicine, 03080, Seoul, Republic of Korea.
  • Pedemonte M; Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
  • Diana MC; Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
  • Baldassari S; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Università Degli Studi di Genova, Genoa, Italy.
  • Zakharova V; Child Neuropsychiatry, IRCCS Istituto G.Gaslini, DINOGMI University of Genova, Largo Gaslini 5, Genoa, Italy.
  • Shcherbina A; Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
  • Rodina Y; Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
  • Fagerberg C; Unit of Medical Genetics, IRCCS Istituto Giannina Gaslini, 16147, Genoa, Italy.
  • Roos LS; National Medical Research Center for Endocrinology, Clinical data analysis department, Moscow, Russian Federation, Russia.
  • Wierzba J; Department of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, 117997, Russia.
  • Dobosz A; Department of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, 117997, Russia.
  • Gerard A; Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
  • Potocki L; Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, København, Denmark.
  • Rosenfeld JA; Department of Pediatrics and Internal Medicine Nursing, Department of Rare Disorders, Medical University of Gdansk, Gdansk, Poland.
  • Lalani SR; Department of Medical Genetics, Faculty of Medicine, Jagiellonian University Medical College, 30-663, Krakow, Poland.
  • Scott TM; Texas Children's Hospital, Houston, TX, USA.
  • Scott D; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
  • Azamian MS; Texas Children's Hospital, Houston, TX, USA.
  • Louie R; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
  • Moore HW; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
  • Champaigne NL; Baylor Genetics Laboratories, Houston, TX, USA.
  • Hollingsworth G; Texas Children's Hospital, Houston, TX, USA.
  • Torella A; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
  • Nigro V; Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, 84112, USA.
  • Ploski R; Baylor Genetics Laboratories, Houston, TX, USA.
  • Salpietro V; Baylor Genetics Laboratories, Houston, TX, USA.
  • Zara F; Greenwood Genetic Center, Greenwood, SC, USA.
  • Pizzi S; Greenwood Genetic Center, Greenwood, SC, USA.
  • Chillemi G; Greenwood Genetic Center, Greenwood, SC, USA.
  • Ognibene M; Greenwood Genetic Center, Greenwood, SC, USA.
  • Cooney E; Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
  • Do J; Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.
  • Linnemann A; Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
  • Larsen MJ; Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.
  • Specht S; Department of Medical Genetics, Medical University of Warsaw, Pawinskiego 3C, 02-106, Warsaw, Poland.
  • Walters KJ; Department of Neuromuscular Disorders, Queen Square Institute of Neurology, University. College London, London, WC1N 3BG, UK.
Nat Commun ; 15(1): 365, 2024 Jan 08.
Article en En | MEDLINE | ID: mdl-38191484
ABSTRACT
WDR44 prevents ciliogenesis initiation by regulating RAB11-dependent vesicle trafficking. Here, we describe male patients with missense and nonsense variants within the WD40 repeats (WDR) of WDR44, an X-linked gene product, who display ciliopathy-related developmental phenotypes that we can model in zebrafish. The patient phenotypic spectrum includes developmental delay/intellectual disability, hypotonia, distinct craniofacial features and variable presence of brain, renal, cardiac and musculoskeletal abnormalities. We demonstrate that WDR44 variants associated with more severe disease impair ciliogenesis initiation and ciliary signaling. Because WDR44 negatively regulates ciliogenesis, it was surprising that pathogenic missense variants showed reduced abundance, which we link to misfolding of WDR autonomous repeats and degradation by the proteasome. We discover that disease severity correlates with increased RAB11 binding, which we propose drives ciliogenesis initiation dysregulation. Finally, we discover interdomain interactions between the WDR and NH2-terminal region that contains the RAB11 binding domain (RBD) and show patient variants disrupt this association. This study provides new insights into WDR44 WDR structure and characterizes a new syndrome that could result from impaired ciliogenesis.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Genes Ligados a X / Ciliopatías / Repeticiones WD40 Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2024 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Genes Ligados a X / Ciliopatías / Repeticiones WD40 Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2024 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Reino Unido