ArticleAnnals of neurology2020
GGPS1 Mutations Cause Muscular Dystrophy/Hearing Loss/Ovarian Insufficiency Syndrome.
Article in Annals of neurology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 39 citations in OpenAlex.
- Skeletal muscle-specific deficiency of Rab geranylgeranyl transferase beta subunit induces myopathy and exacerbates the symptoms caused by HMG-CoA reductase deficiency in mice.Molecular metabolism · 2026Article
- Comprehensive Insights into Perrault Syndrome: Genetic Diversity and Clinical Implications.Reproductive sciences (Thousand Oaks, Calif.) · 2026Review
- Integrative Multi-Omics and Network Analyses Reveal Pathogenic and Protective Pathways in Centronuclear Myopathies.International journal of molecular sciences · 2025Article
- ACSS2 involved in acetyl-CoA synthesis regulates skeletal muscle function.FEBS letters · 2025Article
- Effects of HMG CoA reductase (HMGCR) deficiency on skeletal muscle development.The FEBS journal · 2025Article
- HMGCS1 variants cause rigid spine syndrome amenable to mevalonic acid treatment in an animal model.Brain : a journal of neurology · 2025Article
- Novel compound heterozygous mutations in the LARS2 gene in a Chinese family with hearing loss.Neurogenetics · 2025Article
- Geranylgeranyl Pyrophosphate Promotes Profibrotic Factors and Collagen-Specific Chaperone HSP47 in Fibroblasts.Journal of cellular and molecular medicine · 2024Article
- Exome sequencing in undiagnosed congenital myopathy reveals new genes and refines genes-phenotypes correlations.Genome medicine · 2024Article
- Whole-Genome Scanning for Selection Signatures Reveals Candidate Genes Associated with Growth and Tail Length in Sheep.Animals : an open access journal from MDPI · 2024Article
- Biallelic CRELD1 variants cause a multisystem syndrome, including neurodevelopmental phenotypes, cardiac dysrhythmias, and frequent infections.Genetics in medicine : official journal of the American College of Medical Genetics · 2024Article
- Bi-allelic variants in HMGCR cause an autosomal-recessive progressive limb-girdle muscular dystrophy.American journal of human genetics · 2023Article
- The prognostic role and metabolic function of GGPS1 in oral squamous cell carcinoma.Frontiers in molecular biosciences · 2023Article
- Geranylgeranyl diphosphate synthase: Role in human health, disease and potential therapeutic target.Clinical and translational medicine · 2023Review
- Article
- GGPS1-associated muscular dystrophy with and without hearing loss.Annals of clinical and translational neurology · 2022Article
- Article
- New insights into Perrault syndrome, a clinically and genetically heterogeneous disorder.Human genetics · 2022Review
- Article
- Ggps1 deficiency in the uterus results in dystocia by disrupting uterine contraction.Journal of molecular cell biology · 2021Article
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Authors and funding
34 authors at 17 institutions in 6 countries.
Funding
Abstract
objectiveA 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.
methodsWe 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.
resultsA 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.
interpretationThe 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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