Variants in the WDR44 WD40-repeat domain cause a spectrum of ciliopathy by impairing ciliogenesis initiation.

Autor: Accogli A; Division of Medical Genetics, Department of Specialized Medicine, McGill University Health Centre (MUHC), Montreal, QC, Canada.; Department of Human Genetics, McGill University, Montreal, QC, Canada., Shakya S; Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA., Yang T; Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, 08826, Seoul, Republic of Korea., Insinna C; Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA., Kim SY; Department of Genomic Medicine, Seoul National University Hospital, 03080, Seoul, Republic of Korea., Bell D; Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Butov KR; Department of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, 117997, Russia.; Department of Molecular Biology and Medical Biotechnology, Pirogov Russian National Research Medical University, Moscow, 117997, Russia., Severino M; Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy., Niceta M; Molecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146, Rome, Italy., Scala M; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Università Degli Studi di Genova, Genoa, Italy.; Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy., Lee HS; School of Biological Sciences, Seoul National University, 08826, Seoul, Republic of Korea., Yoo T; Department of Biomedical Sciences, Seoul National University College of Medicine, 03080, Seoul, Republic of Korea., Stauffer J; Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA., Zhao H; Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA., Fiorillo C; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Università Degli Studi di Genova, Genoa, Italy.; Child Neuropsychiatry, IRCCS Istituto G.Gaslini, DINOGMI University of Genova, Largo Gaslini 5, Genoa, Italy., Pedemonte M; Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy., Diana MC; Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy., Baldassari S; Unit of Medical Genetics, IRCCS Istituto Giannina Gaslini, 16147, Genoa, Italy., Zakharova V; National Medical Research Center for Endocrinology, Clinical data analysis department, Moscow, Russian Federation, Russia., Shcherbina A; Department of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, 117997, Russia., Rodina Y; Department of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, 117997, Russia., Fagerberg C; Department of Clinical Genetics, Odense University Hospital, Odense, Denmark., Roos LS; Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, København, Denmark., Wierzba J; Department of Pediatrics and Internal Medicine Nursing, Department of Rare Disorders, Medical University of Gdansk, Gdansk, Poland., Dobosz A; Department of Medical Genetics, Faculty of Medicine, Jagiellonian University Medical College, 30-663, Krakow, Poland., Gerard A; Texas Children's Hospital, Houston, TX, USA.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Potocki L; Texas Children's Hospital, Houston, TX, USA.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Rosenfeld JA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.; Baylor Genetics Laboratories, Houston, TX, USA., Lalani SR; Texas Children's Hospital, Houston, TX, USA.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Scott TM; Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, 84112, USA., Scott D; Baylor Genetics Laboratories, Houston, TX, USA., Azamian MS; Baylor Genetics Laboratories, Houston, TX, USA., Louie R; Greenwood Genetic Center, Greenwood, SC, USA., Moore HW; Greenwood Genetic Center, Greenwood, SC, USA., Champaigne NL; Greenwood Genetic Center, Greenwood, SC, USA., Hollingsworth G; Greenwood Genetic Center, Greenwood, SC, USA., Torella A; Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.; Department of Precision Medicine, University of Campania 'Luigi Vanvitelli', Naples, Italy., Nigro V; Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.; Department of Precision Medicine, University of Campania 'Luigi Vanvitelli', Naples, Italy., Ploski R; Department of Medical Genetics, Medical University of Warsaw, Pawińskiego 3C, 02-106, Warsaw, Poland., Salpietro V; Department of Neuromuscular Disorders, Queen Square Institute of Neurology, University. College London, London, WC1N 3BG, UK.; Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100, L'Aquila, Italy., Zara F; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Università Degli Studi di Genova, Genoa, Italy.; Unit of Medical Genetics, IRCCS Istituto Giannina Gaslini, 16147, Genoa, Italy., Pizzi S; Molecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146, Rome, Italy., Chillemi G; Department for Innovation in Biological, Agro-food and Forest systems, DIBAF, University of Tuscia, Via S. Camillo de Lellis s.n.c, 01100, Viterbo, Italy., Ognibene M; Unit of Medical Genetics, IRCCS Istituto Giannina Gaslini, 16147, Genoa, Italy., Cooney E; Division of Medical Genetics and Metabolism, Department of Pediatrics, University of Texas Medical Branch, Galveston, TX, USA., Do J; Division of Medical Genetics and Metabolism, Department of Pediatrics, University of Texas Medical Branch, Galveston, TX, USA., Linnemann A; Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark., Larsen MJ; Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.; Clinical Genome Center, Department of Clinical Research, University of Southern Denmark, Odense, Denmark., Specht S; Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA., Walters KJ; Center for Structural Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA., Choi HJ; School of Biological Sciences, Seoul National University, 08826, Seoul, Republic of Korea., Choi M; Department of Biomedical Sciences, Seoul National University College of Medicine, 03080, Seoul, Republic of Korea., Tartaglia M; Molecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146, Rome, Italy., Youkharibache P; Cancer Science Data Lab, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Chae JH; Department of Genomic Medicine, Seoul National University Hospital, 03080, Seoul, Republic of Korea., Capra V; Child Neuropsychiatry, IRCCS Istituto G.Gaslini, DINOGMI University of Genova, Largo Gaslini 5, Genoa, Italy., Park SG; Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, 08826, Seoul, Republic of Korea. riceo2@snu.ac.kr., Westlake CJ; Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA. chris.westlake@nih.gov.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Jan 08; Vol. 15 (1), pp. 365. Date of Electronic Publication: 2024 Jan 08.
DOI: 10.1038/s41467-023-44611-2
Abstrakt: 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 NH 2 -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.
(© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
Databáze: MEDLINE
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