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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.<\/jats:p>\n               <jats:p>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 dorso-lumbar 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.<\/jats:p>\n               <jats:p>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\u2019s 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.<\/jats:p>\n               <jats:p>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 wild-type 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.<\/jats:p>\n               <jats:p>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.<\/jats:p>","DOI":"10.1093\/brain\/awae371","type":"journal-article","created":{"date-parts":[[2024,11,12]],"date-time":"2024-11-12T22:51:54Z","timestamp":1731451914000},"page":"1707-1722","source":"Crossref","is-referenced-by-count":6,"title":["HMGCS1 variants cause rigid spine syndrome amenable to mevalonic acid treatment in an animal model"],"prefix":"10.1093","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4381-1909","authenticated-orcid":false,"given":"Lein N H","family":"Dofash","sequence":"first","affiliation":[{"name":"Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia , Perth, WA 6009 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee B","family":"Miles","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Monash University , Melbourne, VIC 3800 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1643-4797","authenticated-orcid":false,"given":"Yoshihiko","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry , Kodaira, Tokyo 187-8502 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eloy","family":"Rivas","sequence":"additional","affiliation":[{"name":"Department of Pathology, Hospital Universitario Virgen del Roc\u00edo Sevilla , Sevilla 41013 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9991-4824","authenticated-orcid":false,"given":"Vanessa","family":"Calcinotto","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Monash University , Melbourne, VIC 3800 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Oveissi","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Monash University , Melbourne, VIC 3800 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0221-2547","authenticated-orcid":false,"given":"Rita J","family":"Serrano","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Monash University , Melbourne, VIC 3800 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Templin","sequence":"additional","affiliation":[{"name":"Ramaciotti Centre for Cryo Electron Microscopy, Monash University , Clayton, VIC 3800 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3596-2288","authenticated-orcid":false,"given":"Georg","family":"Ramm","sequence":"additional","affiliation":[{"name":"Ramaciotti Centre for Cryo Electron Microscopy, Monash University , Clayton, VIC 3800 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison","family":"Rodger","sequence":"additional","affiliation":[{"name":"School of Natural Sciences, Macquarie University , Sydney, NSW 2113 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel","family":"Haywood","sequence":"additional","affiliation":[{"name":"Centre for Crop and Disease Management, School of Molecular and Life Sciences, Curtin University , Perth, WA 6102 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evan","family":"Ingley","sequence":"additional","affiliation":[{"name":"Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia , Perth, WA 6009 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua S","family":"Clayton","sequence":"additional","affiliation":[{"name":"Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia , Perth, WA 6009 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rhonda L","family":"Taylor","sequence":"additional","affiliation":[{"name":"Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia , Perth, WA 6009 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara L","family":"Folland","sequence":"additional","affiliation":[{"name":"Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia , Perth, WA 6009 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Groth","sequence":"additional","affiliation":[{"name":", Curtin University Curtin Medical Research Institute , Perth, WA 6102 ,","place":["Australia"]},{"name":"Curtin Health Innovation Research Institute, Curtin University , Perth, WA 6102 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniella H","family":"Hock","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne , Melbourne, VIC 3010 ,","place":["Australia"]},{"name":"Murdoch Children\u2019s Research Institute, Royal Children\u2019s Hospital , Melbourne, VIC 3052 ,","place":["Australia"]},{"name":"Victorian Clinical Genetics Services, Murdoch Children\u2019s Research Institute , Melbourne, VIC 3052 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A","family":"Stroud","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne , Melbourne, VIC 3010 ,","place":["Australia"]},{"name":"Murdoch Children\u2019s Research Institute, Royal Children\u2019s Hospital , Melbourne, VIC 3052 ,","place":["Australia"]},{"name":"Victorian Clinical Genetics Services, Murdoch Children\u2019s Research Institute , Melbourne, VIC 3052 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6870-4061","authenticated-orcid":false,"given":"Svetlana","family":"Gorokhova","sequence":"additional","affiliation":[{"name":"Aix Marseille Univ, INSERM, Marseille Medical Genetics, U1251, 13385 Marseille ,","place":["France"]},{"name":"Medical Genetics Department, Timone Children\u2019s Hospital, APHM, 13385 Marseille ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Donkervoort","sequence":"additional","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, NINDS, NIH , Bethesda, MD 20892 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten G","family":"B\u00f6nnemann","sequence":"additional","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, NINDS, NIH , Bethesda, MD 20892 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malika","family":"Sud","sequence":"additional","affiliation":[{"name":"Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard , Cambridge, MA 02142 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace E","family":"VanNoy","sequence":"additional","affiliation":[{"name":"Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard , Cambridge, MA 02142 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian E","family":"Mangilog","sequence":"additional","affiliation":[{"name":"Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard , Cambridge, MA 02142 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynn","family":"Pais","sequence":"additional","affiliation":[{"name":"Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard , Cambridge, MA 02142 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"O\u2019Donnell-Luria","sequence":"additional","affiliation":[{"name":"Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard , Cambridge, MA 02142 ,","place":["USA"]},{"name":"Center for Mendelian Genomics, Division of Genetics and Genomics, Department of Pediatrics, Boston Children\u2019s Hospital , Boston, MA 02115 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcos","family":"Madruga-Garrido","sequence":"additional","affiliation":[{"name":"Hospital Viamed Santa \u00c1ngela De la Cruz , Sevilla 41014 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcello","family":"Scala","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova , Genoa 16148 ,","place":["Italy"]},{"name":"Medical Genetics Unit, IRCCS Istituto Giannina Gaslini , Genoa 16147 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Fiorillo","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova , Genoa 16148 ,","place":["Italy"]},{"name":"Child Neuropsichiatry Unit, IRCCS Istituto Giannina Gaslini , Genoa 16147 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena","family":"Baratto","sequence":"additional","affiliation":[{"name":"Center of Translational and Experimental Myology, IRCCS Istituto Giannina Gaslini , Genova 16147 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0606-8797","authenticated-orcid":false,"given":"Monica","family":"Traverso","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, IRCCS Istituto Giannina Gaslini , Genoa 16147 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edoardo","family":"Malfatti","sequence":"additional","affiliation":[{"name":"APHP-Henri Mondor Hospital, Centre de R\u00e9f\u00e9rence de Pathologie Neuromusculaire , Cr\u00e9teil 94000 ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Bruno","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova , Genoa 16148 ,","place":["Italy"]},{"name":"Center of Translational and Experimental Myology, IRCCS Istituto Giannina Gaslini , Genova 16147 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Zara","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova , Genoa 16148 ,","place":["Italy"]},{"name":"Medical Genetics Unit, IRCCS Istituto Giannina Gaslini , Genoa 16147 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6917-2236","authenticated-orcid":false,"given":"Carmen","family":"Paradas","sequence":"additional","affiliation":[{"name":"Department of Neurology, Neuromuscular Unit and Instituto de Biomedicina de Sevilla\/CSIC, Hospital Universitario Virgen del\u202fRoc\u00edo , Sevilla 41013 ,","place":["Spain"]},{"name":"Centro Investigaci\u00f3n Biom\u00e9dica en Red Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III , Sevilla 41092 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsuhisa","family":"Ogata","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Hospital Organization Higashisaitama National Hospital , Hasuda, Saitama 349-0196 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9452-112X","authenticated-orcid":false,"given":"Ichizo","family":"Nishino","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry , Kodaira, Tokyo 187-8502 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nigel G","family":"Laing","sequence":"additional","affiliation":[{"name":"Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia , Perth, WA 6009 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9501-8208","authenticated-orcid":false,"given":"Robert J","family":"Bryson-Richardson","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Monash University , Melbourne, VIC 3800 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