Foley, AR;
Zou, Y;
Dunford, JE;
Rooney, J;
Chandra, G;
Xiong, H;
Straub, V;
... Bonnemann, CG; + view all
(2020)
GGPS1Mutations Cause Muscular Dystrophy/Hearing Loss/Ovarian Insufficiency Syndrome.
Annals of Neurology
10.1002/ana.25772.
(In press).
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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.
| Type: | Article |
|---|---|
| Title: | GGPS1Mutations Cause Muscular Dystrophy/Hearing Loss/Ovarian Insufficiency Syndrome |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/ana.25772 |
| Publisher version: | http://dx.doi.org/10.1002/ana.25772 |
| Language: | English |
| Additional information: | © 2020 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association. 1 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
| Keywords: | GERANYLGERANYL PYROPHOSPHATE SYNTHASE, SENSORINEURAL HEARING-LOSS, VICI SYNDROME, PROTEIN PRENYLATION, DIPHOSPHATE SYNTHASE, CRYSTAL-STRUCTURE, MUTATION, BALANCE, GTPASES, CELLS |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10105171 |
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