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Nat. Commun., 08 January 2024 | https://doi.org/10.1038/s41467-023-44611-2 Variants in the WDR44 WD40-repeat domain cause a spectrum of ciliopathy by impairing ciliogenesis initiation

Andrea Accogli ^1,2,38, Saurabh Shakya ^3,38, Taewoo Yang ^4,38, Christine Insinna ³, Soo Yeon Kim ⁵, David Bell ⁶, Kirill R. Butov ^7,8, Mariasavina Severino ⁹, Marcello Niceta ¹⁰, Marcello Scala ^11,12, Hyun Sik Lee ¹³, Taekyeong Yoo ¹⁴, Jimmy Stauffer ³, Huijie Zhao ³, Chiara Fiorillo ^11,15, Marina Pedemonte ¹², Maria C. Diana ¹², Simona Baldassari ¹⁶, Viktoria Zakharova ¹⁷, Anna Shcherbina ⁷, Yulia Rodina ⁷, Christina Fagerberg ¹⁸, Laura Sønderberg Roos ¹⁹, Jolanta Wierzba ²⁰, Artur Dobosz ²¹, Amanda Gerard ^22,23, Lorraine Potocki ^22,23, Jill A. Rosenfeld ^23,24, Seema R. Lalani ^22,23,Tiana M. Scott ²⁵, Daryl Scott ²⁴, Mahshid S. Azamian²⁴, Raymond Louie ²⁶, Hannah W. Moore ²⁶, Neena L. Champaigne ²⁶, Grace Hollingsworth ²⁶, Annalaura Torella ^27,28, Vincenzo Nigro ^27,28, Rafal Ploski ²⁹, Vincenzo Salpietro ^30,31, Federico Zara ^11,16, Simone Pizzi ¹⁰, Giovanni Chillemi³², Marzia Ognibene ¹⁶, Erin Cooney ³³,Jenny Do ³³, Anders Linnemann ³⁴, Martin J. Larsen 1^8,35, Suzanne Specht ³, Kylie J. Walters ³⁶, Hee-Jung Choi ¹³, Murim Choi ¹⁴, Marco Tartaglia ¹⁰, Phillippe Youkharibache ³⁷, Jong-Hee Chae ⁵, Valeria Capra ¹⁵, Sung-Gyoo Park ^4,*& Christopher J. Westlake ^3,*

¹Division of Medical Genetics, Department of Specialized Medicine, McGill University Health Centre (MUHC), Montreal, QC, Canada.
²Department of Human Genetics, McGill University, Montreal, QC, Canada.
³Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
⁴Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, 08826 Seoul, Republic of Korea.
⁵Department of Genomic Medicine, Seoul National University Hospital, 03080 Seoul, Republic of Korea.
⁶Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
⁷Department of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow 117997, Russia.
⁸Department of Molecular Biology and Medical Biotechnology, Pirogov Russian National Research Medical University, Moscow 117997, Russia.
⁹Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
¹⁰Molecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy. ¹¹Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Università Degli Studi di Genova, Genoa, Italy.
¹²Pediatric Neurology and MuscularDiseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
¹³School of Biological Sciences, Seoul National University, 08826 Seoul, Republic of Korea.
¹⁴Department of Biomedical Sciences, Seoul National University College of Medicine, 03080 Seoul, Republic of Korea. ¹⁵Child Neuropsychiatry, IRCCS Istituto G.Gaslini, DINOGMI University of Genova, Largo Gaslini 5, Genoa, Italy.
¹⁶Unit of Medical Genetics, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy.
¹⁷National Medical Research Center for Endocrinology, Clinical data analysis department, Moscow, Russian Federation, Russia.
¹⁸Department of ClinicalGenetics, Odense University Hospital, Odense, Denmark.
¹⁹Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, København, Denmark.
²⁰Department of Pediatrics and Internal Medicine Nursing, Department of Rare Disorders, Medical University of Gdansk, Gdansk, Poland.
²¹Department of Medical Genetics, Faculty of Medicine, Jagiellonian University Medical College, 30-663 Krakow, Poland. ²²Texas Children’ Hospital, Houston, TX, USA.
²³Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
²⁴Baylor Genetics Laboratories, Houston, TX, USA.
²⁵Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
²⁶Greenwood Genetic Center, Greenwood, SC, USA.
²⁷Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
²⁸Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy.
²⁹Department of Medical Genetics, Medical University of Warsaw, Pawińskiego 3C, 02-106 Warsaw, Poland.
³⁰Department of Neuromuscular Disorders, Queen Square Institute of Neurology, University. College London, London WC1N 3BG, UK.
³¹Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, 67100 L’Aquila, Italy.
³²Department for Innovation in Biological, Agrofood and Forest systems, DIBAF, University of Tuscia, Via S. Camillo de Lellis s.n.c, 01100 Viterbo, Italy.
³³Division of Medical Genetics and Metabolism, Department of Pediatrics, University of Texas Medical Branch, Galveston, TX, USA.
³⁴Hans Christian Andersen Children’s Hospital, Odense University Hospital, Odense, Denmark.
³⁵Clinical Genome Center, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
³⁶Center for Structural Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
³⁷Cancer Science Data Lab, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
³⁸These authors contributed equally: Andrea Accogli, Saurabh Shakya, Taewoo Yang.

^*Corresponding authors: correspondence to Sung-Gyoo Park or Christopher J. Westlake

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.

논문정보

형식Research article
게재일2024년 01월 (BRIC 등록일 2024-01-09)
연구진국내(교신)+국외 연구진
분야 생명과학 > 면역학

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