Variants in the WDR44 WD40-repeat domain cause a spectrum of ciliopathy by impairing ciliogenesis initiation
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...
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-44611-2 |
| _version_ | 1797355667302907904 |
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| author | Andrea Accogli Saurabh Shakya Taewoo Yang Christine Insinna Soo Yeon Kim David Bell Kirill R. Butov Mariasavina Severino Marcello Niceta Marcello Scala Hyun Sik Lee Taekyeong Yoo Jimmy Stauffer Huijie Zhao Chiara Fiorillo Marina Pedemonte Maria C. Diana Simona Baldassari Viktoria Zakharova Anna Shcherbina Yulia Rodina Christina Fagerberg Laura Sønderberg Roos Jolanta Wierzba Artur Dobosz Amanda Gerard Lorraine Potocki Jill A. Rosenfeld Seema R. Lalani Tiana M. Scott Daryl Scott Mahshid S. Azamian Raymond Louie Hannah W. Moore Neena L. Champaigne Grace Hollingsworth Annalaura Torella Vincenzo Nigro Rafal Ploski Vincenzo Salpietro Federico Zara Simone Pizzi Giovanni Chillemi Marzia Ognibene Erin Cooney Jenny Do Anders Linnemann Martin J. Larsen Suzanne Specht Kylie J. Walters Hee-Jung Choi Murim Choi Marco Tartaglia Phillippe Youkharibache Jong-Hee Chae Valeria Capra Sung-Gyoo Park Christopher J. Westlake |
| author_facet | Andrea Accogli Saurabh Shakya Taewoo Yang Christine Insinna Soo Yeon Kim David Bell Kirill R. Butov Mariasavina Severino Marcello Niceta Marcello Scala Hyun Sik Lee Taekyeong Yoo Jimmy Stauffer Huijie Zhao Chiara Fiorillo Marina Pedemonte Maria C. Diana Simona Baldassari Viktoria Zakharova Anna Shcherbina Yulia Rodina Christina Fagerberg Laura Sønderberg Roos Jolanta Wierzba Artur Dobosz Amanda Gerard Lorraine Potocki Jill A. Rosenfeld Seema R. Lalani Tiana M. Scott Daryl Scott Mahshid S. Azamian Raymond Louie Hannah W. Moore Neena L. Champaigne Grace Hollingsworth Annalaura Torella Vincenzo Nigro Rafal Ploski Vincenzo Salpietro Federico Zara Simone Pizzi Giovanni Chillemi Marzia Ognibene Erin Cooney Jenny Do Anders Linnemann Martin J. Larsen Suzanne Specht Kylie J. Walters Hee-Jung Choi Murim Choi Marco Tartaglia Phillippe Youkharibache Jong-Hee Chae Valeria Capra Sung-Gyoo Park Christopher J. Westlake |
| author_sort | Andrea Accogli |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T14:14:28Z |
| format | Article |
| id | doaj.art-af57c8de8d9140e89c63f41fb89329f6 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-08T14:14:28Z |
| publishDate | 2024-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-af57c8de8d9140e89c63f41fb89329f62024-01-14T12:28:51ZengNature PortfolioNature Communications2041-17232024-01-0115112010.1038/s41467-023-44611-2Variants in the WDR44 WD40-repeat domain cause a spectrum of ciliopathy by impairing ciliogenesis initiationAndrea Accogli0Saurabh Shakya1Taewoo Yang2Christine Insinna3Soo Yeon Kim4David Bell5Kirill R. Butov6Mariasavina Severino7Marcello Niceta8Marcello Scala9Hyun Sik Lee10Taekyeong Yoo11Jimmy Stauffer12Huijie Zhao13Chiara Fiorillo14Marina Pedemonte15Maria C. Diana16Simona Baldassari17Viktoria Zakharova18Anna Shcherbina19Yulia Rodina20Christina Fagerberg21Laura Sønderberg Roos22Jolanta Wierzba23Artur Dobosz24Amanda Gerard25Lorraine Potocki26Jill A. Rosenfeld27Seema R. Lalani28Tiana M. Scott29Daryl Scott30Mahshid S. Azamian31Raymond Louie32Hannah W. Moore33Neena L. Champaigne34Grace Hollingsworth35Annalaura Torella36Vincenzo Nigro37Rafal Ploski38Vincenzo Salpietro39Federico Zara40Simone Pizzi41Giovanni Chillemi42Marzia Ognibene43Erin Cooney44Jenny Do45Anders Linnemann46Martin J. Larsen47Suzanne Specht48Kylie J. Walters49Hee-Jung Choi50Murim Choi51Marco Tartaglia52Phillippe Youkharibache53Jong-Hee Chae54Valeria Capra55Sung-Gyoo Park56Christopher J. Westlake57Division of Medical Genetics, Department of Specialized Medicine, McGill University Health Centre (MUHC)Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, National Institutes of HealthInstitute of Pharmaceutical Sciences, College of Pharmacy, Seoul National UniversityLaboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, National Institutes of HealthDepartment of Genomic Medicine, Seoul National University HospitalAdvanced Biomedical Computational Science, Frederick National Laboratory for Cancer ResearchDepartment of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and ImmunologyNeuroradiology Unit, IRCCS Istituto Giannina GasliniMolecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Gesù, IRCCSDepartment of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Università Degli Studi di GenovaSchool of Biological Sciences, Seoul National UniversityDepartment of Biomedical Sciences, Seoul National University College of MedicineLaboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, National Institutes of HealthLaboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, National Institutes of HealthDepartment of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Università Degli Studi di GenovaPediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina GasliniPediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina GasliniUnit of Medical Genetics, IRCCS Istituto Giannina GasliniNational Medical Research Center for Endocrinology, Clinical data analysis departmentDepartment of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and ImmunologyDepartment of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and ImmunologyDepartment of Clinical Genetics, Odense University HospitalDepartment of Clinical Genetics, Rigshospitalet, Copenhagen University HospitalDepartment of Pediatrics and Internal Medicine Nursing, Department of Rare Disorders, Medical University of GdanskDepartment of Medical Genetics, Faculty of Medicine, Jagiellonian University Medical CollegeTexas Children’s HospitalTexas Children’s HospitalDepartment of Molecular and Human Genetics, Baylor College of MedicineTexas Children’s HospitalDivision of Microbiology and Immunology, Department of Pathology, University of Utah School of MedicineBaylor Genetics LaboratoriesBaylor Genetics LaboratoriesGreenwood Genetic CenterGreenwood Genetic CenterGreenwood Genetic CenterGreenwood Genetic CenterTelethon Institute of Genetics and Medicine (TIGEM)Telethon Institute of Genetics and Medicine (TIGEM)Department of Medical Genetics, Medical University of WarsawDepartment of Neuromuscular Disorders, Queen Square Institute of Neurology, University. College LondonDepartment of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Università Degli Studi di GenovaMolecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Gesù, IRCCSDepartment for Innovation in Biological, Agro-food and Forest systems, DIBAF, University of Tuscia, Via S. Camillo de Lellis s.n.cUnit of Medical Genetics, IRCCS Istituto Giannina GasliniDivision of Medical Genetics and Metabolism, Department of Pediatrics, University of Texas Medical BranchDivision of Medical Genetics and Metabolism, Department of Pediatrics, University of Texas Medical BranchHans Christian Andersen Children’s Hospital, Odense University HospitalDepartment of Clinical Genetics, Odense University HospitalLaboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, National Institutes of HealthCenter for Structural Biology, Center for Cancer Research, National Cancer Institute, National Institutes of HealthSchool of Biological Sciences, Seoul National UniversityDepartment of Biomedical Sciences, Seoul National University College of MedicineMolecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Gesù, IRCCSCancer Science Data Lab, Center for Cancer Research, National Cancer Institute, National Institutes of HealthDepartment of Genomic Medicine, Seoul National University HospitalChild Neuropsychiatry, IRCCS Istituto G.Gaslini, DINOGMI University of GenovaInstitute of Pharmaceutical Sciences, College of Pharmacy, Seoul National UniversityLaboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, National Institutes of HealthAbstract 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.https://doi.org/10.1038/s41467-023-44611-2 |
| spellingShingle | Andrea Accogli Saurabh Shakya Taewoo Yang Christine Insinna Soo Yeon Kim David Bell Kirill R. Butov Mariasavina Severino Marcello Niceta Marcello Scala Hyun Sik Lee Taekyeong Yoo Jimmy Stauffer Huijie Zhao Chiara Fiorillo Marina Pedemonte Maria C. Diana Simona Baldassari Viktoria Zakharova Anna Shcherbina Yulia Rodina Christina Fagerberg Laura Sønderberg Roos Jolanta Wierzba Artur Dobosz Amanda Gerard Lorraine Potocki Jill A. Rosenfeld Seema R. Lalani Tiana M. Scott Daryl Scott Mahshid S. Azamian Raymond Louie Hannah W. Moore Neena L. Champaigne Grace Hollingsworth Annalaura Torella Vincenzo Nigro Rafal Ploski Vincenzo Salpietro Federico Zara Simone Pizzi Giovanni Chillemi Marzia Ognibene Erin Cooney Jenny Do Anders Linnemann Martin J. Larsen Suzanne Specht Kylie J. Walters Hee-Jung Choi Murim Choi Marco Tartaglia Phillippe Youkharibache Jong-Hee Chae Valeria Capra Sung-Gyoo Park Christopher J. Westlake Variants in the WDR44 WD40-repeat domain cause a spectrum of ciliopathy by impairing ciliogenesis initiation Nature Communications |
| title | Variants in the WDR44 WD40-repeat domain cause a spectrum of ciliopathy by impairing ciliogenesis initiation |
| title_full | Variants in the WDR44 WD40-repeat domain cause a spectrum of ciliopathy by impairing ciliogenesis initiation |
| title_fullStr | Variants in the WDR44 WD40-repeat domain cause a spectrum of ciliopathy by impairing ciliogenesis initiation |
| title_full_unstemmed | Variants in the WDR44 WD40-repeat domain cause a spectrum of ciliopathy by impairing ciliogenesis initiation |
| title_short | Variants in the WDR44 WD40-repeat domain cause a spectrum of ciliopathy by impairing ciliogenesis initiation |
| title_sort | variants in the wdr44 wd40 repeat domain cause a spectrum of ciliopathy by impairing ciliogenesis initiation |
| url | https://doi.org/10.1038/s41467-023-44611-2 |
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