{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T08:39:50Z","timestamp":1790498390572,"version":"4.1.0"},"reference-count":48,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2020,6,18]],"date-time":"2020-06-18T00:00:00Z","timestamp":1592438400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2020,8]]},"abstract":"Objective<\/jats:title>A hitherto undescribed phenotype of early onset muscular dystrophy associated with sensorineural hearing loss and primary ovarian insufficiency was initially identified in 2 siblings and in subsequent patients with a similar constellation of findings. The goal of this study was to understand the genetic and molecular etiology of this condition.<\/jats:p><\/jats:sec>Methods<\/jats:title>We applied whole exome sequencing (WES) superimposed on shared haplotype regions to identify the initial biallelic variants in GGPS1<\/jats:italic> followed by GGPS1<\/jats:italic> Sanger sequencing or WES in 5 additional families with the same phenotype. Molecular modeling, biochemical analysis, laser membrane injury assay, and the generation of a Y259C knock\u2010in mouse were done.<\/jats:p><\/jats:sec>Results<\/jats:title>A total of 11 patients in 6 families carrying 5 different biallelic pathogenic variants in specific domains of GGPS1<\/jats:italic> were identified. GGPS1<\/jats:italic> encodes geranylgeranyl diphosphate synthase in the mevalonate\/isoprenoid pathway, which catalyzes the synthesis of geranylgeranyl pyrophosphate, the lipid precursor of geranylgeranylated proteins including small guanosine triphosphatases. In addition to proximal weakness, all but one patient presented with congenital sensorineural hearing loss, and all postpubertal females had primary ovarian insufficiency. Muscle histology was dystrophic, with ultrastructural evidence of autophagic material and large mitochondria in the most severe cases. There was delayed membrane healing after laser injury in patient\u2010derived myogenic cells, and a knock\u2010in mouse of one of the mutations (Y259C) resulted in prenatal lethality.<\/jats:p><\/jats:sec>Interpretation<\/jats:title>The identification of specific GGPS1<\/jats:italic> mutations defines the cause of a unique form of muscular dystrophy with hearing loss and ovarian insufficiency and points to a novel pathway for this clinical constellation. ANN NEUROL 2020;88:332\u2013347.<\/jats:bold><\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.25772","type":"journal-article","created":{"date-parts":[[2020,5,14]],"date-time":"2020-05-14T00:34:13Z","timestamp":1589416453000},"page":"332-347","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["GGPS1<\/i><\/scp> Mutations Cause Muscular Dystrophy\/Hearing Loss\/Ovarian Insufficiency Syndrome"],"prefix":"10.1002","volume":"88","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2168-1119","authenticated-orcid":false,"given":"A. Reghan","family":"Foley","sequence":"first","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section National Institute of Neurological Disorders and Stroke, National Institutes of Health Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaqun","family":"Zou","sequence":"additional","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section National Institute of Neurological Disorders and Stroke, National Institutes of Health Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James E.","family":"Dunford","sequence":"additional","affiliation":[{"name":"Botnar Research Centre, National Institute for Health Research Biomedical Research Centre Oxford University of Oxford Oxford United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jachinta","family":"Rooney","sequence":"additional","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section National Institute of Neurological Disorders and Stroke, National Institutes of Health Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Goutam","family":"Chandra","sequence":"additional","affiliation":[{"name":"Children's National Health System Center for Genetic Medicine Research Washington District of Columbia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Xiong","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Peking University First Hospital Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Volker","family":"Straub","sequence":"additional","affiliation":[{"name":"Institute of Genetic Medicine International Centre for Life Newcastle upon Tyne United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Voit","sequence":"additional","affiliation":[{"name":"Great Ormond Street Hospital Biomedical Research Centre Great Ormond Street Institute of Child Health, University College London London United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norma","family":"Romero","sequence":"additional","affiliation":[{"name":"National Institute of Health and Medical Research U974, Sorbonne University Institute of Myology, APHP Paris France"},{"name":"Neuromuscular Morphology Unit Institute of Myology, Piti\u00e9\u2010Salp\u00eatri\u00e8re Hospital Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Donkervoort","sequence":"additional","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section National Institute of Neurological Disorders and Stroke, National Institutes of Health Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Hu","sequence":"additional","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section National Institute of Neurological Disorders and Stroke, National Institutes of Health Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Markello","sequence":"additional","affiliation":[{"name":"National Institutes of Health Undiagnosed Diseases Program National Human Genome Research Institute Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Horn","sequence":"additional","affiliation":[{"name":"Children's National Health System Center for Genetic Medicine Research Washington District of Columbia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leila","family":"Qebibo","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics and Oncogenetics University Hospital Fes Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jahannaz","family":"Dastgir","sequence":"additional","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section National Institute of Neurological Disorders and Stroke, National Institutes of Health Bethesda Maryland USA"},{"name":"Department of Pediatric Neurology Goryeb Children's Hospital Morristown New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine G.","family":"Meilleur","sequence":"additional","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section National Institute of Neurological Disorders and Stroke, National Institutes of Health Bethesda Maryland USA"},{"name":"Biogen Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard S.","family":"Finkel","sequence":"additional","affiliation":[{"name":"Division of Neurology Children's Hospital of Philadelphia Philadelphia Pennsylvania USA"},{"name":"Translational Neuroscience Program St. Jude Children\u2019s Research Hospital Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanbin","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Peking University First Hospital Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamel","family":"Mamchaoui","sequence":"additional","affiliation":[{"name":"National Institute of Health and Medical Research U974, Sorbonne University Institute of Myology, APHP Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Duguez","sequence":"additional","affiliation":[{"name":"National Institute of Health and Medical Research U974, Sorbonne University Institute of Myology, APHP Paris France"},{"name":"School of Biomedical Sciences Ulster University Derry United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Nelson","sequence":"additional","affiliation":[{"name":"National Institute of Health and Medical Research U974, Sorbonne University Institute of Myology, APHP Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8256-5862","authenticated-orcid":false,"given":"Jocelyn","family":"Laporte","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Molecular and Cellular Biology, National Institute of Health and Medical Research U1258, National Center for Scientific Research UMR7104 University of Strasbourg Illkirch France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariarita","family":"Santi","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Children's Hospital of Philadelphia Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edoardo","family":"Malfatti","sequence":"additional","affiliation":[{"name":"National Institute of Health and Medical Research U974, Sorbonne University Institute of Myology, APHP Paris France"},{"name":"U1179 University of Versailles Saint\u2010Quentin\u2010en\u2010Yvelines\u2010National Institute of Health and Medical Research Paris\u2010Saclay University Versailles France"},{"name":"Neurology Department, Reference Center for Neuromuscular Diseases North\/East\/Ile de France Raymond\u2010Poincar\u00e9 University Hospital Garches France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thierry","family":"Maisonobe","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurophysiology Piti\u00e9\u2010Salp\u00eatri\u00e8re Hospital Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Touraine","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Reproductive Medicine, Faculty of Medicine, Sorbonne University, Piti\u00e9\u2010Salp\u00eatri\u00e8re Hospital, APHP Reference Center for Rare Endocrine Diseases of Growth and Development and Reference Center for Rare Gynecologic Disorders Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michio","family":"Hirano","sequence":"additional","affiliation":[{"name":"Department of Neurology, H. Houston Merritt Neuromuscular Research Center Columbia University Medical Center New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imelda","family":"Hughes","sequence":"additional","affiliation":[{"name":"Department of Paediatric Neurology Royal Manchester Children's Hospital Manchester United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate","family":"Bushby","sequence":"additional","affiliation":[{"name":"Institute of Genetic Medicine International Centre for Life Newcastle upon Tyne United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Udo","family":"Oppermann","sequence":"additional","affiliation":[{"name":"Botnar Research Centre, National Institute for Health Research Biomedical Research Centre Oxford University of Oxford Oxford United Kingdom"},{"name":"Structural Genomics Consortium University of Oxford Oxford United Kingdom"},{"name":"Freiburg Institute of Advanced Studies University of Freiburg Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8019-9504","authenticated-orcid":false,"given":"Johann","family":"B\u00f6hm","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Molecular and Cellular Biology, National Institute of Health and Medical Research U1258, National Center for Scientific Research UMR7104 University of Strasbourg Illkirch France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5992-5185","authenticated-orcid":false,"given":"Jyoti K.","family":"Jaiswal","sequence":"additional","affiliation":[{"name":"Children's National Health System Center for Genetic Medicine Research Washington District of Columbia USA"},{"name":"Department of Genomics and Precision Medicine George Washington University School of Medicine and Health Sciences Washington District of Columbia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanya","family":"Stojkovic","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Sorbonne University, Piti\u00e9\u2010Salp\u00eatri\u00e8re Hospital, APHP Reference Center for Neuromuscular Diseases North\/East\/Ile de France Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5930-2324","authenticated-orcid":false,"given":"Carsten G.","family":"B\u00f6nnemann","sequence":"additional","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section National Institute of Neurological Disorders and Stroke, National Institutes of Health Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,6,18]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)32910-1"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-444-64076-5.00035-1"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12776"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/343425a0"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11427-015-4836-1"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-005-5298-6"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/cdg571"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.05560"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M090548"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc1612804"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbm4.10024"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.3580"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-019-0434-0"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.50882"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M602603200"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aaj1978"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/jb\/mvm162"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)54009-6"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20121806"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.repbio.2019.10.001"},{"key":"e_1_2_8_22_1","doi-asserted-by":"crossref","unstructured":"EgilmezOK KalciogluMT. Genetics of nonsyndromic congenital hearing loss. Scientifica (Cairo) 2016;2016:7576064.","DOI":"10.1155\/2016\/7576064"},{"key":"e_1_2_8_23_1","doi-asserted-by":"crossref","unstructured":"DumanD TekinM. Autosomal recessive nonsyndromic deafness genes: a review. Front Biosci (Landmark Ed).2012;17:2213\u20132236.","DOI":"10.2741\/4046"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3182a84140"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.33296"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.34244"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pediatrneurol.2012.07.007"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-016-0399-x"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2017.05.005"},{"key":"e_1_2_8_30_1","article-title":"Biallelic variants in LARS2 and KARS cause deafness and (ovario) leukodystrophy","volume":"92","author":"Knaap MS","year":"2019","journal-title":"Neurology"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.015909"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-018-2888-7"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/149.2.1051"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2011.277"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.4480"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep28917"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1006535"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.657742"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2016.01.021"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1515161"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.2174\/157488609789006949"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm9010022"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.2174\/1381612033453640"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbm4.10064"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M512886200"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.03306"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/35103068"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.114.001271"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2014.12.042"}],"container-title":["Annals of Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fana.25772","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ana.25772","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ana.25772","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ana.25772","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T16:45:47Z","timestamp":1692981947000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ana.25772"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,18]]},"references-count":48,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2020,8]]}},"alternative-id":["10.1002\/ana.25772"],"URL":"https:\/\/doi.org\/10.1002\/ana.25772","archive":["Portico"],"relation":{},"ISSN":["0364-5134","1531-8249"],"issn-type":[{"value":"0364-5134","type":"print"},{"value":"1531-8249","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,18]]},"assertion":[{"value":"2020-02-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-05-06","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-06-18","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}