The Genotypic and Phenotypic Spectrum of GOSR2 Mutations: Clinical and Pathophysiological Insights

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• North Sea-Progressive Myoclonus Epilepsy (NS-PME) is a rare neurological disorder initially linked to a specific GOSR2 mutation.
• Clinical manifestations include early-onset ataxia, myoclonus, and epilepsy.
• Recent findings indicate a broader spectrum of GOSR2 mutations and associated phenotypes.

Purpose of the Study:

• To systematically review GOSR2 mutations and associated clinical phenotypes.
• To enhance genotype-phenotype predictions for NS-PME patients.
• To improve clinical care and identify potential therapeutic avenues.

Main Methods:

• A narrative literature review was conducted using PubMed, EMBASE, and Web of Science (1985-August 2024).
• Keywords included "GOSR2", "GS27 protein", "Bos1", and "Membrin".
• Studies focused on GOSR2 function, pathogenic variants, clinical manifestations, and therapies were included.

Main Results:

• 42 patients with 11 distinct GOSR2 mutations were identified.
• Key phenotypes include progressive myoclonus ataxia/epilepsy, congenital muscular dystrophy, and hearing loss.
• GOSR2 mutations cause partial or complete loss of function in the GOSR2/SNARE complex, leading to phenotypic variability.

Conclusions:

• The genotypic basis of NS-PME is broader than previously thought, involving various biallelic GOSR2 variants.
• Understanding GOSR2-related disease mechanisms is crucial for targeted treatments and accurate phenotype prediction.
• This review consolidates current knowledge to guide future research and clinical management.