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

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.

Ggps1 deficiency in the uterus results in dystocia by disrupting uterine contraction

“…In their work, a total of 11 patients in 6 families carrying five different biallelic mutations in specific domains of GGPS1 were identified. All post-pubertal females had primary ovarian insufficiency, which is consistent with our genetic work in animal model ( Jiang et al, 2017 ; Foley et al, 2020 ), revealing that Ggps1 is essential for early folliculogenesis and oocyte maturation in female fertility. Primary ovarian insufficiency might cause female infertility, that is possibly why no females with Ggps1 mutations are found in human dystocia.…”

“…Recent studies reveal that GGPS1 mutations cause muscular dystrophy/hearing loss/ovarian insufficiency syndrome ( Foley et al, 2020 ), indicating GGPS1 has a critical role in human. In their work, a total of 11 patients in 6 families carrying five different biallelic mutations in specific domains of GGPS1 were identified.…”

New insights into Perrault syndrome, a clinically and genetically heterogeneous disorder

“…GGPS1 encodes a cytosolic and perhaps mitochondrial, geranylgeranyl diphosphate (GGPP) synthase. There appears to be some colocalization of GGPS1 with ATP synthase beta, a marker for mitochondria (Foley et al 2020). In 11 patients of six unrelated families, Foley and coauthors described a new syndrome manifesting with early-onset, progressive muscular dystrophy, likely congenital deafness and POI with a menopausal level of FSH (Foley et al 2020).…”

“…The fertility status of five deaf males in these families is unknown. GGPS1 is expressed in testes and reduced expression of GGPS1 is associated with infertility in men (Bae et al 2019;Foley et al 2020;Wang et al 2013). Eight of the 11 affected subjects had short stature and a failure to thrive.…”

Identification of Novel Candidate Genes and Variants for Hearing Loss and Temporal Bone Anomalies

“…A large community of clinicians and scientists continues to identify novel genes and variants for syndromic and nonsyndromic hearing loss. In the past two years alone, variants within novel hearing loss genes including SLC9A3R1, ANLN, FOXF2, TOP2B, PLS1, PISD, CLRN2, AP1B1, SCD5, GGPS1, SLC12A2, THOC1 and GREB1L were identified in patients of various ethnicities [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. To date, some of these genes remain candidates that require replication in additional hearing loss families and patients [6,9,14,19].…”