Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders.

Autor:	Kaiyrzhanov R; Department of Neuromuscular Diseases, UCL Institute of Neurology, London WC1N 3BG, UK., Rad A; Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar 009851, Iran.; Tübingen Hearing Research Centre, Department of Otolaryngology, Head and Neck Surgery, Eberhard Karls University, 72076 Tübingen, Germany., Lin SJ; Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA., Bertoli-Avella A; Department of Medical Genetics, CENTOGENE GmbH, 18055 Rostock, Germany., Kallemeijn WW; Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, London W12 0BZ, UK.; Chemical Biology and Therapeutic Discovery Lab, The Francis Crick Institute, London NW1 1AT, UK., Godwin A; European Xenopus Resource Centre-XenMD, School of Biological Sciences, University of Portsmouth, Portsmouth PO1 2DT, UK., Zaki MS; Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, 12622 Cairo, Egypt., Huang K; Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA., Lau T; Department of Neuromuscular Diseases, UCL Institute of Neurology, London WC1N 3BG, UK., Petree C; Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA., Efthymiou S; Department of Neuromuscular Diseases, UCL Institute of Neurology, London WC1N 3BG, UK., Karimiani EG; Genetics Research Centre, Molecular and Clinical Sciences Institute, St George's University of London, London SW17 0RE, UK.; Department of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad 1696700, Iran., Hempel M; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.; Institute of Human Genetics, University Hospital Heidelberg, Heidelberg 69120, Germany., Normand EA; Clinical Genomics Program, GeneDx, Gaithersburg, MD 20877, USA., Rudnik-Schöneborn S; Institute of Human Genetics, Medical University Innsbruck, Innsbruck 6020, Austria., Schatz UA; Institute of Human Genetics, Medical University Innsbruck, Innsbruck 6020, Austria.; Institute of Human Genetics, Technical University of Munich, Munich, 81675, Germany., Baggelaar MP; Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, London W12 0BZ, UK.; Biomolecular Mass Spectrometry & Proteomics Group, Utrecht University, 3584 CH Utrecht, The Netherlands., Ilyas M; Department of BioEngineering, University of Engineering and Applied Sciences, 19130 Swat, Pakistan.; Centre for Omic Sciences, Islamia College University, 25000 Peshawar, Pakistan., Sultan T; Department of Pediatric Neurology, Institute of Child Health, Children Hospital, Lahore 54600, Pakistan., Alvi JR; Department of Pediatric Neurology, Institute of Child Health, Children Hospital, Lahore 54600, Pakistan., Ganieva M; Department of Neurology, Avicenna Tajik State Medical University, 734063 Dushanbe, Tajikistan., Fowler B; Imaging Core, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA., Aanicai R; Department of Medical Genetics, CENTOGENE GmbH, 18055 Rostock, Germany., Tayfun GA; Department of Pediatric Genetics, Marmara University Medical School, 34722 Istanbul, Turkey., Al Saman A; Pediatric Neurology Department, National Neuroscience Institute, King Fahad Medical City, 49046 Riyadh, Saudi Arabia., Alswaid A; King Saud Bin Abdulaziz University for Health Sciences, Department of Pediatrics, King Abdullah Specialized Children's Hospital, Riyadh 11461, Saudi Arabia., Amiri N; International Collaboration on Repair Discoveries (ICORD), University of British Columbia, Vancouver, BC V5Z 1M9, Canada., Asilova N; Department of Neurology, Avicenna Tajik State Medical University, 734063 Dushanbe, Tajikistan., Shotelersuk V; Center of Excellence for Medical Genomics, Department of Pediatrics, King Chulalongkorn Memorial Hospital, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand., Yeetong P; Division of Human Genetics, Department of Botany, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand., Azam M; Pediatrics and Child Neurology, Wah Medical College, 47000 Wah Cantt, Pakistan., Babaei M; Department of Pediatrics, North Khorasan University of Medical Sciences, Bojnurd 94149-74877, Iran., Monajemi GB; Pars Advanced and Minimally Invasive Medical Manners Research Center, Pars Hospital, Tehran, Iran., Mohammadi P; Children's Medical Center, Pediatrics Center of Excellence, Ataxia Clinic, Tehran University of Medical Sciences, Tehran 1416634793, Iran.; Faculty of Medical Sciences, Department of Medical Genetics, Tarbiat Modares University, Tehran 1411944961, Iran., Samie S; Pars Advanced and Minimally Invasive Medical Manners Research Center, Pars Hospital, Tehran, Iran., Banu SH; Department of Paediatric Neurology and Development, Dr. M.R. Khan Shishu (Children) Hospital and Institute of Child Health, Dhaka 1216, Bangladesh., Pinto Basto J; Department of Medical Genetics, CENTOGENE GmbH, 18055 Rostock, Germany., Kortüm F; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Bauer M; Division of Clinical Genetics and Metabolism, Nicklas Children's Hospital, Miami, FL 33155, USA., Bauer P; Department of Medical Genetics, CENTOGENE GmbH, 18055 Rostock, Germany., Beetz C; Department of Medical Genetics, CENTOGENE GmbH, 18055 Rostock, Germany., Garshasbi M; Faculty of Medical Sciences, Department of Medical Genetics, Tarbiat Modares University, Tehran 1411944961, Iran., Issa AH; Department of Neurology, University of Basrah, 61004 Basrah, Iraq., Eyaid W; Department of Genetics and Precision Medicine, King Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Science, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs (NGHA), Riyadh 11426, Saudi Arabia., Ahmed H; Department of Genetics and Precision Medicine, King Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Science, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs (NGHA), Riyadh 11426, Saudi Arabia., Hashemi N; Department of Pediatrics, School of Medicine, Mashhad University of Medical Sciences, 13131-99137 Mashhad, Iran., Hassanpour K; Non-Communicable Diseases Research Center, Sabzevar University of Medical Sciences, 319 Sabzevar, Iran., Herman I; Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX 68010, USA.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.; Department of Neurology, Texas Children's Hospital, Houston, TX 77030, USA.; Pediatric Neurology, Neurogenetics and Rare Diseases, Boys Town National Research Hospital, Boys Town, NE 68131, USA., Ibrohimov S; Department of Neurology, Avicenna Tajik State Medical University, 734063 Dushanbe, Tajikistan., Abdul-Majeed BA; Molecular Pathology and Genetics, The Pioneer Molecular Pathology Lab, Baghdad 10044, Iraq., Imdad M; Centre for Human Genetics, Hazara University, 21300 Mansehra, Pakistan., Isrofilov M; Department of Neurology, Avicenna Tajik State Medical University, 734063 Dushanbe, Tajikistan., Kaiyal Q; Department of Pediatric Neurology, Clalit Health Care, 2510500 Haifa, Israel., Khan S; Department of Medical Genetics, CENTOGENE GmbH, 18055 Rostock, Germany., Kirmse B; SOM-Peds-Genetics, University of Mississippi Medical Center, Jackson MS, 39216, USA., Koster J; Laboratory Genetic Metabolic Diseases, Amsterdam University Medical Centers location AMC, 1100 DD Amsterdam, The Netherlands., Lourenço CM; Faculdade de Medicina, Centro Universitario Estácio de Ribeirão Preto, 14096-160 São Paulo, Brazil., Mitani T; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Moldovan O; Serviço de Genética Médica, Departamento de Pediatria, Hospital de Santa Maria, Centro Hospitalar Universitário de Lisboa Norte, 1649-035 Lisboa, Portugal., Murphy D; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK., Najafi M; Pediatrics Genetics Division, Center for Pediatrics and Adolescent Medicine, Faculty of Medicine, Freiburg University, 79106 Freiburg, Germany.; Genome Research Division, Human Genetics Department, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands., Pehlivan D; Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX 68010, USA.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Rocha ME; Department of Medical Genetics, CENTOGENE GmbH, 18055 Rostock, Germany., Salpietro V; Department of Neuromuscular Diseases, UCL Institute of Neurology, London WC1N 3BG, UK., Schmidts M; Pediatrics Genetics Division, Center for Pediatrics and Adolescent Medicine, Faculty of Medicine, Freiburg University, 79106 Freiburg, Germany.; Genome Research Division, Human Genetics Department, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands.; CIBSS-Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany., Shalata A; Pediatrics and Medical Genetics, the Simon Winter Institute for Human Genetics, Bnai Zion Medical Center, 31048 Haifa, Israel.; Bruce Rappaport Faculty of Medicine, the Technion institution of Technology, 3200003 Haifa, Israel., Mahroum M; CIBSS-Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany., Talbeya JK; Pediatrics and Medical Genetics, the Simon Winter Institute for Human Genetics, Bnai Zion Medical Center, 31048 Haifa, Israel.; Department of Radiology, The Bnai Zion Medical Center, Haifa 31048, Israel., Taylor RW; Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.; NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK., Vazquez D; Division of Clinical Genetics and Metabolism, Nicklas Children's Hospital, Miami, FL 33155, USA., Vetro A; Neuroscience Department, Meyer Children's Hospital IRCCS, 50139 Florence, Italy., Waterham HR; Laboratory Genetic Metabolic Diseases, Amsterdam University Medical Centers location AMC, 1100 DD Amsterdam, The Netherlands., Zaman M; Department of Paediatric Neurology and Development, Dr. M.R. Khan Shishu (Children) Hospital and Institute of Child Health, Dhaka 1216, Bangladesh., Schrader TA; Department of Biosciences, University of Exeter, Exeter EX4 4QD, UK., Chung WK; Department of Pediatrics, Columbia University Irving Medical Center, New York, NY 10032, USA.; Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA., Guerrini R; Neuroscience Department, Meyer Children's Hospital IRCCS, 50139 Florence, Italy.; Neuroscience, Pharmacology and Child Health Department, University of Florence, 50139 Florence, Italy., Lupski JR; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.; Department of Neurology, Texas Children's Hospital, Houston, TX 77030, USA.; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA., Gleeson J; Department of Neurosciences, University of California, San Diego, CA 92093, USA.; Department of Neurosciences, Rady Children's Institute for Genomic Medicine, San Diego, CA 92025, USA., Suri M; Clinical Genetics Service, Nottingham University Hospitals NHS Trust, Nottingham NG5 1PB, UK., Jamshidi Y; Genetics Research Centre, Molecular and Clinical Sciences Institute, St George's University of London, London SW17 0RE, UK.; Human Genetics Centre of Excellence, Novo Nordisk Research Centre Oxford, Oxford, OX3 7FZ, UK., Bhatia KP; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK., Vona B; Tübingen Hearing Research Centre, Department of Otolaryngology, Head and Neck Surgery, Eberhard Karls University, 72076 Tübingen, Germany.; Institute of Human Genetics, University Medical Center Göttingen, 37073 Göttingen, Germany.; Institute for Auditory Neuroscience and Inner Ear Lab, University Medical Center Göttingen, 37075 Göttingen, Germany., Schrader M; Department of Biosciences, University of Exeter, Exeter EX4 4QD, UK., Severino M; Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy., Guille M; European Xenopus Resource Centre-XenMD, School of Biological Sciences, University of Portsmouth, Portsmouth PO1 2DT, UK., Tate EW; Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, London W12 0BZ, UK.; Chemical Biology and Therapeutic Discovery Lab, The Francis Crick Institute, London NW1 1AT, UK., Varshney GK; Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA., Houlden H; Department of Neuromuscular Diseases, UCL Institute of Neurology, London WC1N 3BG, UK., Maroofian R; Department of Neuromuscular Diseases, UCL Institute of Neurology, London WC1N 3BG, UK.
Jazyk:	angličtina
Zdroj:	Brain : a journal of neurology [Brain] 2024 Apr 04; Vol. 147 (4), pp. 1436-1456.
DOI:	10.1093/brain/awad380
Abstrakt:	The acyl-CoA-binding domain-containing protein 6 (ACBD6) is ubiquitously expressed, plays a role in the acylation of lipids and proteins and regulates the N-myristoylation of proteins via N-myristoyltransferase enzymes (NMTs). However, its precise function in cells is still unclear, as is the consequence of ACBD6 defects on human pathophysiology. Using exome sequencing and extensive international data sharing efforts, we identified 45 affected individuals from 28 unrelated families (consanguinity 93%) with bi-allelic pathogenic, predominantly loss-of-function (18/20) variants in ACBD6. We generated zebrafish and Xenopus tropicalis acbd6 knockouts by CRISPR/Cas9 and characterized the role of ACBD6 on protein N-myristoylation with myristic acid alkyne (YnMyr) chemical proteomics in the model organisms and human cells, with the latter also being subjected further to ACBD6 peroxisomal localization studies. The affected individuals (23 males and 22 females), aged 1-50 years, typically present with a complex and progressive disease involving moderate-to-severe global developmental delay/intellectual disability (100%) with significant expressive language impairment (98%), movement disorders (97%), facial dysmorphism (95%) and mild cerebellar ataxia (85%) associated with gait impairment (94%), limb spasticity/hypertonia (76%), oculomotor (71%) and behavioural abnormalities (65%), overweight (59%), microcephaly (39%) and epilepsy (33%). The most conspicuous and common movement disorder was dystonia (94%), frequently leading to early-onset progressive postural deformities (97%), limb dystonia (55%) and cervical dystonia (31%). A jerky tremor in the upper limbs (63%), a mild head tremor (59%), parkinsonism/hypokinesia developing with advancing age (32%) and simple motor and vocal tics were among other frequent movement disorders. Midline brain malformations including corpus callosum abnormalities (70%), hypoplasia/agenesis of the anterior commissure (66%), short midbrain and small inferior cerebellar vermis (38% each) as well as hypertrophy of the clava (24%) were common neuroimaging findings. Acbd6-deficient zebrafish and Xenopus models effectively recapitulated many clinical phenotypes reported in patients including movement disorders, progressive neuromotor impairment, seizures, microcephaly, craniofacial dysmorphism and midbrain defects accompanied by developmental delay with increased mortality over time. Unlike ACBD5, ACBD6 did not show a peroxisomal localization and ACBD6-deficiency was not associated with altered peroxisomal parameters in patient fibroblasts. Significant differences in YnMyr-labelling were observed for 68 co- and 18 post-translationally N-myristoylated proteins in patient-derived fibroblasts. N-myristoylation was similarly affected in acbd6-deficient zebrafish and X. tropicalis models, including Fus, Marcks and Chchd-related proteins implicated in neurological diseases. The present study provides evidence that bi-allelic pathogenic variants in ACBD6 lead to a distinct neurodevelopmental syndrome accompanied by complex and progressive cognitive and movement disorders. (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu