Contributors: Biological and Environmental Science and Engineering (BESE) Division; Bioscience Program; Computational Bioscience Research Center (CBRC); Structural Biology and Engineering; Department of Clinical Genetics, Erasmus MC University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands; Department of Genetics, King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh, 11211, Kingdom of Saudi Arabia; KACST-BWH/Harvard Centre of Excellence for Biomedicine, Joint Centers of Excellence Program, King Abdulaziz City for Science and Technology, Riyadh 12354, Saudi Arabia; Department of Medical Genetics, King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh, 11211, Kingdom of Saudi Arabia; Department of Biology, Imam Abdulrahman bin Faisal University, Dammam 34212, Kingdom of Saudi Arabia; Genome Research Division, Human Genetics Department, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, The Netherlands; Center for Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg University, Faculty of Medicine, Freiburg 79106, Germany; Department of Neurosciences, KFSHRC, Riyadh, 11211, Kingdom of Saudi Arabia; Department of Pathology and Laboratory Medicine, KFSHRC, Riyadh, 11211, Kingdom of Saudi Arabia; Positivo University Medical School, Curitiba, Parana, 81280-330, Brazil; Universidade da Região de Joinville, Pós-Graduação em Saúde e Meio Ambiente, Joinville, Santa Catarina, 89219-710, Brazil; Núcleo de Assistência Integral ao Paciente Especial, Prefeitura de Joinvile, Joinvile, Santa Catarina, 89202-450, Brazil; Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, 9177899191, Mashhad, Iran; CENTOGENE GmbH, 18055 Rostock, Germany; Medical University of Rostock, 18051 Rostock, Germany; Stem Cell and Tissue Re-engineering Program, KFSHRC, Riyadh, 11211, Kingdom of Saudi Arabia; Gaziosmanpasa University, School of Medicine, Neurology Dept. Tokat, 8FJH+CW Tokat, Merkez/Tokat, Turkey; Koc University, School of Medicine, Suna and Inan Kirac Foundation, NDAL- KUTTAM, Davutpasa cad. No.4, 34010, Zeytinburnu, İstanbul, Turkey; Department of Molecular Neuroscience, University College London Institute of Neurology, London WC1N 3BG, UK; Department of Molecular and Human Genetics, Baylor College of Medicine, and Baylor Genetics Laboratories, Houston, TX, USA; Molecular and Clinical Sciences Institute, St. George’s, University of London, Cranmer Terrace, London SW17 0RE, UK; Innovative Medical Research Center, Mashhad Branch, Islamic Azad University, 9G58 + 69 Mashhad, Razavi Khorasan Province, Iran; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Kingdom of Saudi Arabia; Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, 11211, Riyadh, Kingdom of Saudi Arabia; Department of Cell Biology, KFSHRC, Riyadh, 11211, Kingdom of Saudi Arabia; Centre de Biochimie Structurale, CNRS, INSERM, Université de Montpellier, 34090 Montpellier, France; Department of Biostatistics, Epidemiology and Scientific Computing, KFSHRC, Riyadh, 11211, Kingdom of Saudi Arabia; Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK
نبذة مختصرة : Membrane trafficking is a complex, essential process in eukaryotic cells responsible for protein transport and processing. Deficiencies in vacuolar protein sorting (VPS) proteins, key regulators of trafficking, cause abnormal intracellular segregation of macromolecules and organelles and are linked to human disease. VPS proteins function as part of complexes such as the homotypic fusion and vacuole protein sorting (HOPS) tethering complex, composed of VPS11, VPS16, VPS18, VPS33A, VPS39 and VPS41. The HOPS-specific subunit VPS41 has been reported to promote viability of dopaminergic neurons in Parkinson's disease but to date has not been linked to human disease. Here, we describe five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function. All affected individuals presented with a progressive neurodevelopmental disorder consisting of cognitive impairment, cerebellar atrophy/hypoplasia, motor dysfunction with ataxia and dystonia, and nystagmus. Zebrafish disease modelling supports the involvement of VPS41 dysfunction in the disorder, indicating lysosomal dysregulation throughout the brain and providing support for cerebellar and microglial abnormalities when vps41 was mutated. This provides the first example of human disease linked to the HOPS-specific subunit VPS41 and suggests the importance of HOPS complex activity for cerebellar function. ; We are grateful to the families for their participation. We thank the Saudi Human Genome Program, Core Facilities, and Purchasing Departments at King Faisal Specialist Hospital and Research Center (KFSHRC) and special thanks to Mr Faisal Al-Otaibi for quickly handling our orders and requests. Wim Quint and Kirke Tadema (Erasmus MC) are acknowledged for their expertise in OKR analysis.
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