GGPS1 Mutations Cause Muscular Dystrophy/Hearing Loss/Ovarian Insufficiency Syndrome

Ann Neurol. 2020 Aug;88(2):332-347. doi: 10.1002/ana.25772.

A Reghan Foley ¹, Yaqun Zou ¹, James E Dunford ², Jachinta Rooney ¹, Goutam Chandra ³, Hui Xiong ⁴, Volker Straub ⁵, Thomas Voit ⁶, Norma Romero ⁷ ⁸, Sandra Donkervoort ¹, Ying Hu ¹, Thomas Markello ⁹, Adam Horn ³, Leila Qebibo ¹⁰, Jahannaz Dastgir ¹ ¹¹, Katherine G Meilleur ¹ ¹², Richard S Finkel ¹³ ¹⁴, Yanbin Fan ⁴, Kamel Mamchaoui ⁷, Stephanie Duguez ⁷ ¹⁵, Isabelle Nelson ⁷, Jocelyn Laporte ¹⁶, Mariarita Santi ¹⁷, Edoardo Malfatti ⁷ ¹⁸ ¹⁹, Thierry Maisonobe ²⁰, Philippe Touraine ²¹, Michio Hirano ²², Imelda Hughes ²³, Kate Bushby ⁵, Udo Oppermann ² ²⁴ ²⁵, Johann Böhm ¹⁶, Jyoti K Jaiswal ³ ²⁶, Tanya Stojkovic ²⁷, Carsten G Bönnemann ¹

Affiliations

1 Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
2 Botnar Research Centre, National Institute for Health Research Biomedical Research Centre Oxford, University of Oxford, Oxford, United Kingdom.
3 Children's National Health System, Center for Genetic Medicine Research, Washington, District of Columbia, USA.
4 Department of Pediatrics, Peking University First Hospital, Beijing, China.
5 Institute of Genetic Medicine, International Centre for Life, Newcastle upon Tyne, United Kingdom.
6 Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.
7 National Institute of Health and Medical Research U974, Sorbonne University, Institute of Myology, APHP, Paris, France.
8 Neuromuscular Morphology Unit, Institute of Myology, Pitié-Salpêtrière Hospital, Paris, France.
9 National Institutes of Health Undiagnosed Diseases Program, National Human Genome Research Institute, Bethesda, Maryland, USA.
10 Unit of Medical Genetics and Oncogenetics, University Hospital, Fes, Morocco.
11 Department of Pediatric Neurology, Goryeb Children's Hospital, Morristown, New Jersey, USA.
12 Biogen, Cambridge, Massachusetts, USA.
13 Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
14 Translational Neuroscience Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
15 School of Biomedical Sciences, Ulster University, Derry, United Kingdom.
16 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.
17 Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
18 U1179 University of Versailles Saint-Quentin-en-Yvelines-National Institute of Health and Medical Research, Paris-Saclay University, Versailles, France.
19 Neurology Department, Reference Center for Neuromuscular Diseases North/East/Ile de France, Raymond-Poincaré University Hospital, Garches, France.
20 Department of Clinical Neurophysiology, Pitié-Salpêtrière Hospital, Paris, France.
21 Department of Endocrinology and Reproductive Medicine, Faculty of Medicine, Sorbonne University, Pitié-Salpêtrière Hospital, APHP, Reference Center for Rare Endocrine Diseases of Growth and Development and Reference Center for Rare Gynecologic Disorders, Paris, France.
22 Department of Neurology, H. Houston Merritt Neuromuscular Research Center , Columbia University Medical Center, New York, New York, USA.
23 Department of Paediatric Neurology, Royal Manchester Children's Hospital, Manchester, United Kingdom.
24 Structural Genomics Consortium, University of Oxford, Oxford, United Kingdom.
25 Freiburg Institute of Advanced Studies, University of Freiburg, Freiburg, Germany.
26 Department of Genomics and Precision Medicine, George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA.
27 Faculty of Medicine, Sorbonne University, Pitié-Salpêtrière Hospital, APHP, Reference Center for Neuromuscular Diseases North/East/Ile de France, Paris, France.

PMID: 32403198 DOI: 10.1002/ana.25772

Abstract

Objective: 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.

Methods: We applied whole exome Sequencing (WES) superimposed on shared haplotype regions to identify the initial biallelic variants in GGPS1 followed by GGPS1 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-in mouse were done.

Results: A total of 11 patients in 6 families carrying 5 different biallelic pathogenic variants in specific domains of GGPS1 were identified. GGPS1 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-derived myogenic cells, and a knock-in mouse of one of the mutations (Y259C) resulted in prenatal lethality.

Interpretation: The identification of specific GGPS1 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;88:332-347.

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