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Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders.
Kaiyrzhanov, Rauan; Rad, Aboulfazl; Lin, Sheng-Jia; Bertoli-Avella, Aida; Kallemeijn, Wouter W; Godwin, Annie; Zaki, Maha S; Huang, Kevin; Lau, Tracy; Petree, Cassidy; Efthymiou, Stephanie; Karimiani, Ehsan Ghayoor; Hempel, Maja; Normand, Elizabeth A; Rudnik-Schöneborn, Sabine; Schatz, Ulrich A; Baggelaar, Marc P; Ilyas, Muhammad; Sultan, Tipu; Alvi, Javeria Raza; Ganieva, Manizha; Fowler, Ben; Aanicai, Ruxandra; Tayfun, Gulsen Akay; Al Saman, Abdulaziz; Alswaid, Abdulrahman; Amiri, Nafise; Asilova, Nilufar; Shotelersuk, Vorasuk; Yeetong, Patra; Azam, Matloob; Babaei, Meisam; Monajemi, Gholamreza Bahrami; Mohammadi, Pouria; Samie, Saeed; Banu, Selina Husna; Pinto Basto, Jorge; Kortüm, Fanny; Bauer, Mislen; Bauer, Peter; Beetz, Christian; Garshasbi, Masoud; Issa, Awatif Hameed; Eyaid, Wafaa; Ahmed, Hind; Hashemi, Narges; Hassanpour, Kazem; Herman, Isabella; Ibrohimov, Sherozjon; Abdul-Majeed, Ban A.
Afiliação
  • 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.
  • Lin SJ; Tübingen Hearing Research Centre, Department of Otolaryngology, Head and Neck Surgery, Eberhard Karls University, 72076 Tübingen, Germany.
  • Bertoli-Avella A; Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
  • Kallemeijn WW; Department of Medical Genetics, CENTOGENE GmbH, 18055 Rostock, Germany.
  • Godwin A; Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, London W12 0BZ, UK.
  • Zaki MS; Chemical Biology and Therapeutic Discovery Lab, The Francis Crick Institute, London NW1 1AT, UK.
  • Huang K; European Xenopus Resource Centre-XenMD, School of Biological Sciences, University of Portsmouth, Portsmouth PO1 2DT, UK.
  • Lau T; Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, 12622 Cairo, Egypt.
  • 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; Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
  • Hempel M; Department of Neuromuscular Diseases, UCL Institute of Neurology, London WC1N 3BG, UK.
  • Normand EA; Genetics Research Centre, Molecular and Clinical Sciences Institute, St George's University of London, London SW17 0RE, UK.
  • Rudnik-Schöneborn S; Department of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad 1696700, Iran.
  • Schatz UA; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • Baggelaar MP; Institute of Human Genetics, University Hospital Heidelberg, Heidelberg 69120, Germany.
  • Ilyas M; Clinical Genomics Program, GeneDx, Gaithersburg, MD 20877, USA.
  • Sultan T; Institute of Human Genetics, Medical University Innsbruck, Innsbruck 6020, Austria.
  • Alvi JR; Institute of Human Genetics, Medical University Innsbruck, Innsbruck 6020, Austria.
  • Ganieva M; Institute of Human Genetics, Technical University of Munich, Munich, 81675, Germany.
  • Fowler B; Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, London W12 0BZ, UK.
  • Aanicai R; Biomolecular Mass Spectrometry & Proteomics Group, Utrecht University, 3584 CH Utrecht, The Netherlands.
  • Tayfun GA; Department of BioEngineering, University of Engineering and Applied Sciences, 19130 Swat, Pakistan.
  • Al Saman A; Centre for Omic Sciences, Islamia College University, 25000 Peshawar, Pakistan.
  • Alswaid A; Department of Pediatric Neurology, Institute of Child Health, Children Hospital, Lahore 54600, Pakistan.
  • Amiri N; Department of Pediatric Neurology, Institute of Child Health, Children Hospital, Lahore 54600, Pakistan.
  • Asilova N; Department of Neurology, Avicenna Tajik State Medical University, 734063 Dushanbe, Tajikistan.
  • Shotelersuk V; Imaging Core, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
  • Yeetong P; Department of Medical Genetics, CENTOGENE GmbH, 18055 Rostock, Germany.
  • Azam M; Department of Pediatric Genetics, Marmara University Medical School, 34722 Istanbul, Turkey.
  • Babaei M; Pediatric Neurology Department, National Neuroscience Institute, King Fahad Medical City, 49046 Riyadh, Saudi Arabia.
  • Monajemi GB; King Saud Bin Abdulaziz University for Health Sciences, Department of Pediatrics, King Abdullah Specialized Children's Hospital, Riyadh 11461, Saudi Arabia.
  • Mohammadi P; International Collaboration on Repair Discoveries (ICORD), University of British Columbia, Vancouver, BC V5Z 1M9, Canada.
  • Samie S; Department of Neurology, Avicenna Tajik State Medical University, 734063 Dushanbe, Tajikistan.
  • Banu SH; Center of Excellence for Medical Genomics, Department of Pediatrics, King Chulalongkorn Memorial Hospital, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.
  • Pinto Basto J; Division of Human Genetics, Department of Botany, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
  • Kortüm F; Pediatrics and Child Neurology, Wah Medical College, 47000 Wah Cantt, Pakistan.
  • Bauer M; Department of Pediatrics, North Khorasan University of Medical Sciences, Bojnurd 94149-74877, Iran.
  • Bauer P; Pars Advanced and Minimally Invasive Medical Manners Research Center, Pars Hospital, Tehran, Iran.
  • Beetz C; Children's Medical Center, Pediatrics Center of Excellence, Ataxia Clinic, Tehran University of Medical Sciences, Tehran 1416634793, Iran.
  • Garshasbi M; Faculty of Medical Sciences, Department of Medical Genetics, Tarbiat Modares University, Tehran 1411944961, Iran.
  • Issa AH; Pars Advanced and Minimally Invasive Medical Manners Research Center, Pars Hospital, Tehran, Iran.
  • Eyaid W; Department of Paediatric Neurology and Development, Dr. M.R. Khan Shishu (Children) Hospital and Institute of Child Health, Dhaka 1216, Bangladesh.
  • Ahmed H; Department of Medical Genetics, CENTOGENE GmbH, 18055 Rostock, Germany.
  • Hashemi N; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • Hassanpour K; Division of Clinical Genetics and Metabolism, Nicklas Children's Hospital, Miami, FL 33155, USA.
  • Herman I; Department of Medical Genetics, CENTOGENE GmbH, 18055 Rostock, Germany.
  • Ibrohimov S; Department of Medical Genetics, CENTOGENE GmbH, 18055 Rostock, Germany.
  • Abdul-Majeed BA; Faculty of Medical Sciences, Department of Medical Genetics, Tarbiat Modares University, Tehran 1411944961, Iran.
Brain ; 147(4): 1436-1456, 2024 Apr 04.
Article em En | MEDLINE | ID: mdl-37951597
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Transtornos do Neurodesenvolvimento / Deficiência Intelectual / Microcefalia / Transtornos dos Movimentos / Malformações do Sistema Nervoso Limite: Adolescent / Adult / Animals / Child / Child, preschool / Female / Humans / Infant / Male / Middle aged Idioma: En Revista: Brain Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Transtornos do Neurodesenvolvimento / Deficiência Intelectual / Microcefalia / Transtornos dos Movimentos / Malformações do Sistema Nervoso Limite: Adolescent / Adult / Animals / Child / Child, preschool / Female / Humans / Infant / Male / Middle aged Idioma: En Revista: Brain Ano de publicação: 2024 Tipo de documento: Article