HMGCS1 variants cause rigid spine syndrome amenable to mevalonic acid treatment in an animal model.

Autor: Dofash LNH; Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, Perth, WA 6009, Australia., Miles LB; School of Biological Sciences, Monash University, Melbourne, VIC 3800, Australia., Saito Y; Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan., Rivas E; Department of Pathology, Hospital Universitario Virgen del Rocío Sevilla  41013, Spain., Calcinotto V; School of Biological Sciences, Monash University, Melbourne, VIC 3800, Australia., Oveissi S; School of Biological Sciences, Monash University, Melbourne, VIC 3800, Australia., Serrano RJ; School of Biological Sciences, Monash University, Melbourne, VIC 3800, Australia., Templin R; Ramaciotti Centre for Cryo Electron Microscopy, Monash University, Clayton, VIC 3800, Australia., Ramm G; Ramaciotti Centre for Cryo Electron Microscopy, Monash University, Clayton, VIC 3800, Australia., Rodger A; School of Natural Sciences, Macquarie University, Sydney, NSW 2113, Australia., Haywood J; Centre for Crop and Disease Management, School of Molecular and Life Sciences, Curtin University, Bentley, Perth, WA 6102, Australia., Ingley E; Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, Perth, WA 6009, Australia., Clayton JS; Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, Perth, WA 6009, Australia., Taylor RL; Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, Perth, WA 6009, Australia., Folland CL; Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, Perth, WA 6009, Australia., Groth D; Curtin Medical School, Curtin University; Curtin Health Innovation Research Institute, Curtin University, Bentley, Perth, WA 6102, Australia., Hock DH; Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, VIC 3010, Australia.; Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia., Stroud DA; Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, VIC 3010, Australia.; Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia., Gorokhova S; Marseille Medical Genetics Université, INSERM, U 1251, Aix-Marseille Université, Marseille 13005, France.; Department of Medical Genetics, Hôpital Timone Enfants, APHM, Marseille 13385, France., Donkervoort S; Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, NINDS, NIH, Bethesda, MD 20892, USA., Bönnemann CG; Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, NINDS, NIH, Bethesda, MD 20892, USA., Sud M; Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., VanNoy GE; Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Mangilog BE; Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Pais L; Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., O'Donnell-Luria A; Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Center for Mendelian Genomics, Division of Genetics & Genomics, Department of Pediatrics, Boston Children's Hospital, MA 02115, USA., Madruga-Garrido M; Hospital Viamed Santa Ángela De la Cruz, Sevilla 41014, Spain., Scala M; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genoa 16148, Italy.; Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa 16147, Italy., Fiorillo C; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genoa 16148, Italy.; Child Neuropsichiatry Unit, IRCCS Istituto Giannina Gaslini; Genoa 16147, Italy., Baratto S; Center of Translational and Experimental Myology, IRCCS Istituto Giannina Gaslini, Genova 16147, Italy., Traverso M; Pediatric Neurology and Muscle Disease Unit, IRCCS Istituto Giannina Gaslini, Genova 16147, Italy., Malfatti E; APHP, Centre de Référence de Pathologie Neuromusculaire Nord-Est-Ile-de-France, Paris 75014, France.; Henri Mondor Hospital, France; Université Paris Est, U955, INSERM, IMRB, F-94010 Créteil 94000, France., Bruno C; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genoa 16148, Italy.; Center of Translational and Experimental Myology, IRCCS Istituto Giannina Gaslini, Genova 16147, Italy., Zara F; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genoa 16148, Italy.; Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa 16147, Italy., Paradas C; Department of Neurology, Neuromuscular Unit and Instituto de Biomedicina de Sevilla/CSIC, Hospital Universitario Virgen del Rocío, Sevilla 41013, Spain.; Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Sevilla 41092, Spain., Ogata K; Department of Neurology, National Hospital Organization Higashisaitama National Hospital, Hasuda, Saitama 349-0196, Japan., Nishino I; Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan., Laing NG; Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, Perth, WA 6009, Australia., Bryson-Richardson RJ; School of Biological Sciences, Monash University, Melbourne, VIC 3800, Australia., Cabrera-Serrano M; Department of Neurology, Neuromuscular Unit and Instituto de Biomedicina de Sevilla/CSIC, Hospital Universitario Virgen del Rocío, Sevilla 41013, Spain.; Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Sevilla 41092, Spain., Ravenscroft G; Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, Perth, WA 6009, Australia.
Jazyk: angličtina
Zdroj: Brain : a journal of neurology [Brain] 2024 Nov 12. Date of Electronic Publication: 2024 Nov 12.
DOI: 10.1093/brain/awae371
Abstrakt: Rigid spine syndrome is a rare childhood-onset myopathy characterised by slowly progressive or non-progressive scoliosis, neck and spine contractures, hypotonia, and respiratory insufficiency. Biallelic variants in SELENON account for most cases of rigid spine syndrome, however, the underlying genetic cause in some patients remains unexplained. We used exome and genome sequencing to investigate the genetic basis of rigid spine syndrome in patients without a genetic diagnosis. In five patients from four unrelated families, we identified biallelic variants in HMGCS1 (3-hydroxy-3-methylglutaryl-coenzyme A synthase). These included six missense variants and one frameshift variant distributed throughout HMGCS1. All patients presented with spinal rigidity primarily affecting the cervical and dorsolumbar regions, scoliosis, and respiratory insufficiency. Creatine kinase levels were variably elevated. The clinical course worsened with intercurrent disease or certain drugs in some patients; one patient died from respiratory failure following infection. Muscle biopsies revealed irregularities in oxidative enzyme staining with occasional internal nuclei and rimmed vacuoles. HMGCS1 encodes a critical enzyme of the mevalonate pathway and has not yet been associated with disease. Notably, biallelic hypomorphic variants in downstream enzymes including HMGCR and GGPS1 are associated with muscular dystrophy resembling our cohort's presentation. Analyses of recombinant human HMGCS1 protein and four variants (p.S447P, p.Q29L, p.M70T, p.C268S) showed that all mutants maintained their dimerization state. Three of the four mutants exhibited reduced thermal stability, and two mutants showed subtle changes in enzymatic activity compared to the wildtype. Hmgcs1 mutant zebrafish displayed severe early defects, including immobility at 2 days and death by day 3 post-fertilisation and were rescued by HMGCS1 mRNA. We demonstrate that the four variants tested (S447P, Q29L M70T, and C268S) have reduced function compared to wildtype HMGCS1 in zebrafish rescue assays. Additionally, we demonstrate the potential for mevalonic acid supplementation to reduce phenotypic severity in mutant zebrafish. Overall, our analyses suggest that these missense variants in HMGCS1 act through a hypomorphic mechanism. Here, we report an additional component of the mevalonate pathway associated with disease and suggest biallelic variants in HMGCS1 should be considered in patients presenting with an unresolved rigid spine myopathy phenotype. Additionally, we highlight mevalonoic acid supplementation as a potential treatment for patients with HMGCS1-related disease.
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Databáze: MEDLINE
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