Mutations in GGPS1 gene cause novel form of muscular dystrophy

Researchers have identified mutations in the GGPS1 gene as the cause of a novel form of muscular dystrophy associated with hearing loss and ovarian insufficiency, according to findings published in Annals of Neurology.

“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 researchers wrote. “The goal of this study was to understand the genetic and molecular etiology of this condition.”

A. Reghan Foley, MD, of the Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, at the NIH, and colleagues noted that congenital sensorineural hearing loss rarely manifests in association with muscular dystrophy, although it has been reported in early-onset facioscapulohumeral muscular dystrophy.

The researchers applied whole exome sequencing superimposed on haplotype regions to pinpoint initial biallelic variants in GGPS1 followed by GGPS1 Sanger sequencing or whole exome sequencing in 5 additional families with the same phenotype.

Foley and colleagues identified a total of 11 patients from 6 families with 5 different biallelic pathogenic variants in specific domains of GGPS1. All but one patient presented with congenital sensorineural hearing loss and all post-pubertal women had primary ovarian insufficiency.

Muscle histology was dystrophic, with ultrastructural evidence of autophagic material and large mitochondria in the most severe cases, according to Foley and colleagues. The researchers identified delayed membrane healing following laser injury in patient-derived myogenic cells.

“Biallelic, highly specific missense mutations in GGPS1 in 11 patients from 6 independent families define a unique new syndrome of muscular dystrophy with associated congenital sensorineural hearing loss and primary ovarian insufficiency in females, while also highlighting the mevalonate/isoprenoid pathway as a novel, albeit still incompletely explored, pathway for muscular dystrophy, hearing loss and infertility,” the researchers wrote. “Because of the fundamental role GGPPS plays in cellular processes at all levels, it is likely that the effects of the mutations described here will be highly specific as to their cellular mutations in muscle, inner ear and ovary.”

Foley and colleagues also noted that increased understanding and greater awareness of these novel mechanisms and pathways could also “open avenues for therapeutic intervention.”