ArticleNature communications2024
Variants in the WDR44 WD40-repeat domain cause a spectrum of ciliopathy by impairing ciliogenesis initiation.
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Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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10 citing papers in PubMed, 10 citations in OpenAlex.
- Research Progress on the Pathogenesis and Diagnostic and Therapeutic Potential of Ciliopathies Regulated by IFT172.Clinical genetics · 2026Review
- Primary cilium disassembly - from mechanisms to roles in physiology and disease.Journal of cell science · 2026Review
- Characterization of membrane structures regulating primary ciliogenesis by quantitative isotropic ultrastructure imaging.Nature communications · 2026Article
- WDR44 drives de novo α-synuclein aggregation at the lysosomal membrane and promotes neuronal dysfunction in Parkinson's Disease.bioRxiv : the preprint server for biology · 2026Article
- Telethon Undiagnosed Disease Program: Structured approach to solving rare childhood-onset genetic diseases.Genetics in medicine open · 2026Article
- Primary cilia gene defects in BMSCs induce idiopathic scoliosis.Cellular and molecular life sciences : CMLS · 2025Article
- Musculoskeletal deformities of Alström syndrome-a review of 55 cases.Orphanet journal of rare diseases · 2025Article
- TBC1D20 coordinates vesicle transport and actin remodeling to regulate ciliogenesis.The Journal of cell biology · 2025Article
- WDR44 Loss-of-Function Promoter Deletion in a Male Newborn With a Ciliopathy Phenotype.American journal of medical genetics. Part A · 2025Article
- Rab11-Rab8 cascade dynamics in primary cilia and membrane tubules.Cell reports · 2024Article
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Authors and funding
58 authors at 20 institutions in 9 countries.
Andrea Accogli *Division of Medical Genetics, Department of Specialized Medicine, McGill University Health Centre (MUHC), Montreal, QC, Canada.
Saurabh Shakya *Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.ORCID 0009-0006-5005-6100
Taewoo Yang *Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, 08826, Seoul, Republic of Korea.
Christine InsinnaLaboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
Soo Yeon KimDepartment of Genomic Medicine, Seoul National University Hospital, 03080, Seoul, Republic of Korea.
David BellAdvanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
Kirill R ButovDepartment of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, 117997, Russia.
Mariasavina SeverinoNeuroradiology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
Marcello NicetaMolecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146, Rome, Italy.ORCID 0000-0003-4766-7753
Marcello ScalaDepartment of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Università Degli Studi di Genova, Genoa, Italy.ORCID 0000-0003-2194-7239
Hyun Sik LeeSchool of Biological Sciences, Seoul National University, 08826, Seoul, Republic of Korea.ORCID 0000-0002-3550-7894
Taekyeong YooDepartment of Biomedical Sciences, Seoul National University College of Medicine, 03080, Seoul, Republic of Korea.
Jimmy StaufferLaboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
Huijie ZhaoLaboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.ORCID 0000-0002-8595-8159
Chiara FiorilloDepartment of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Università Degli Studi di Genova, Genoa, Italy.
Marina PedemontePediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
Maria C DianaPediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
Simona BaldassariUnit of Medical Genetics, IRCCS Istituto Giannina Gaslini, 16147, Genoa, Italy.
Viktoria ZakharovaNational Medical Research Center for Endocrinology, Clinical data analysis department, Moscow, Russian Federation, Russia.ORCID 0000-0001-5949-5317
Anna ShcherbinaDepartment of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, 117997, Russia.
Yulia RodinaDepartment of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, 117997, Russia.
Christina FagerbergDepartment of Clinical Genetics, Odense University Hospital, Odense, Denmark.ORCID 0000-0002-5206-4327
Laura Sønderberg RoosDepartment of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, København, Denmark.
Jolanta WierzbaDepartment of Pediatrics and Internal Medicine Nursing, Department of Rare Disorders, Medical University of Gdansk, Gdansk, Poland.
Artur DoboszDepartment of Medical Genetics, Faculty of Medicine, Jagiellonian University Medical College, 30-663, Krakow, Poland.
Amanda GerardTexas Children's Hospital, Houston, TX, USA.
Lorraine PotockiTexas Children's Hospital, Houston, TX, USA.
Jill A RosenfeldDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.ORCID 0000-0001-5664-7987
Seema R LalaniTexas Children's Hospital, Houston, TX, USA.
Tiana M ScottDivision of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, 84112, USA.
Daryl ScottBaylor Genetics Laboratories, Houston, TX, USA.ORCID 0000-0003-1460-5169
Mahshid S AzamianBaylor Genetics Laboratories, Houston, TX, USA.ORCID 0000-0002-8543-8284
Raymond LouieGreenwood Genetic Center, Greenwood, SC, USA.
Hannah W MooreGreenwood Genetic Center, Greenwood, SC, USA.
Neena L ChampaigneGreenwood Genetic Center, Greenwood, SC, USA.
Grace HollingsworthGreenwood Genetic Center, Greenwood, SC, USA.
Annalaura TorellaTelethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
Vincenzo NigroTelethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
Rafal PloskiDepartment of Medical Genetics, Medical University of Warsaw, Pawińskiego 3C, 02-106, Warsaw, Poland.
Vincenzo SalpietroDepartment of Neuromuscular Disorders, Queen Square Institute of Neurology, University. College London, London, WC1N 3BG, UK.ORCID 0000-0003-0132-7921
Federico ZaraDepartment of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Università Degli Studi di Genova, Genoa, Italy.ORCID 0000-0001-9744-5222
Simone PizziMolecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146, Rome, Italy.
Giovanni ChillemiDepartment for Innovation in Biological, Agro-food and Forest systems, DIBAF, University of Tuscia, Via S. Camillo de Lellis s.n.c, 01100, Viterbo, Italy.ORCID 0000-0003-3901-6926
Marzia OgnibeneUnit of Medical Genetics, IRCCS Istituto Giannina Gaslini, 16147, Genoa, Italy.ORCID 0000-0003-3698-9319
Erin CooneyDivision of Medical Genetics and Metabolism, Department of Pediatrics, University of Texas Medical Branch, Galveston, TX, USA.
Jenny DoDivision of Medical Genetics and Metabolism, Department of Pediatrics, University of Texas Medical Branch, Galveston, TX, USA.
Anders LinnemannHans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark.
Martin J LarsenDepartment of Clinical Genetics, Odense University Hospital, Odense, Denmark.ORCID 0000-0003-4107-8771
Suzanne SpechtLaboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
Kylie J WaltersCenter for Structural Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.ORCID 0000-0001-7590-2891
Hee-Jung ChoiSchool of Biological Sciences, Seoul National University, 08826, Seoul, Republic of Korea.ORCID 0000-0002-1167-1526
Murim ChoiDepartment of Biomedical Sciences, Seoul National University College of Medicine, 03080, Seoul, Republic of Korea.ORCID 0000-0002-9195-1455
Marco TartagliaMolecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146, Rome, Italy.ORCID 0000-0001-7736-9672
Phillippe YoukharibacheCancer Science Data Lab, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Jong-Hee ChaeDepartment of Genomic Medicine, Seoul National University Hospital, 03080, Seoul, Republic of Korea.
Valeria CapraChild Neuropsychiatry, IRCCS Istituto G.Gaslini, DINOGMI University of Genova, Largo Gaslini 5, Genoa, Italy.
Sung-Gyoo ParkInstitute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, 08826, Seoul, Republic of Korea. riceo2@snu.ac.kr.ORCID 0000-0003-3702-5765
Christopher J WestlakeLaboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA. chris.westlake@nih.gov.ORCID 0000-0001-7476-2014
Istituto Giannina Gaslini · ITNational Institutes of Health · USSeoul National University · KRBaylor College of Medicine · USGreenwood Genetic Center · USBambino Gesù Children's Hospital · ITBaylor Genetics · USDmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology · RUOdense University Hospital · DKSeoul National University Hospital · KRThe University of Texas Medical Branch at Galveston · USUniversity of Campania "Luigi Vanvitelli" · ITCopenhagen University Hospital · DKFrederick National Laboratory for Cancer Research · USGdańsk Medical University · PLJagiellonian University · PLMcGill University Health Centre · CAMedical University of Warsaw · PLPirogov Russian National Research Medical University · RUUniversità degli Studi della Tuscia · IT
Funding
Ubiquitin signaling for protein degradationZIABC011490 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI WALTERS, KYLIE · 2013 to 2025
$21.1MRegulation of Ciliogenesis and Ciliary-related signalingZIABC011398 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI WESTLAKE, CHRISTOPHER · 2011 to 2025
$18.7MMyosin VI: a new ubiquitin receptorZIABC011627 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI WALTERS, KYLIE · 2015 to 2025
$4.6MZebrafish coreZICBC011956 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI KETTENHOFEN, CHRISTINE · 2020 to 2025
$4.4MStructural data science methods and software to study immunotherapeutic proteinsZIHBC012005 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI YOUKHARIBACHE, PHILIPPE · 2020 to 2024
$753kNCI NIH HHS HHSN261200800001EWellcome Trust
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 NH
Indexed as
CiliopathiesGenes, X-LinkedWD40 RepeatsAnimalsBrainCognitionHumansMaleZebrafish
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