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

## TL;DR

This paper reviews the range of GOSR2 mutations and their effects, expanding the known clinical and genetic features of a neurological disorder.

## Contribution

The study expands the genotypic and phenotypic spectrum of GOSR2 mutations beyond the original founder mutation.

## Key findings

- Three main phenotypes were identified: progressive myoclonus ataxia/epilepsy, congenital muscular dystrophy, and hearing loss.
- Glycosylation defects were reported in several compound heterozygous GOSR2 variants.
- GOSR2 mutations lead to a partial loss of function of the GOSR2/SNARE complex, contributing to phenotypic variability.

## Abstract

North Sea‐Progressive Myoclonus Epilepsy (NS‐PME) is a progressive neurological disorder, initially only associated with the homozygous GOSR2 founder mutation (c.430G>T; p.Gly144Trp). Clinical symptoms include untreatable early‐onset ataxia, cortical myoclonus and epilepsy. Recently, the spectrum of GOSR2 mutations and associated phenotypic variability has expanded. To improve care and to facilitate genotype–phenotype predictions for NS‐PME patients, we systematically reviewed all reported GOSR2 mutations, clinical phenotypes, and pathophysiological findings. A narrative review literature search was conducted in PubMed, EMBASE, and Web of Science (1985—August 2024) using the keywords “GOSR2”, “GS27 protein”, “Bos1”, and “Membrin”. Only studies in English and specifically studies on GOSR2 function, pathogenic variants, clinical manifestations, and potential therapies were included. A total of 42 patients with 11 different GOSR2 mutations were identified. Three main phenotypes were observed: progressive myoclonus ataxia/epilepsy (PMA/PME), congenital muscular dystrophy, and hearing loss. Orthopedic abnormalities were frequently reported. Intercurrent infections or fever often led to a worsening of symptoms. Glycosylation defects were reported in several compound heterozygous GOSR2 variants. Molecularly, GOSR2 mutations result in (partial) loss of function of the GOSR2/SNARE complex, with mutation severity and the involvement of specific isoforms contributing to phenotypic variability. GOSR2 mutations lead to progressive neurological disorders, primarily characterized by myoclonus ataxia/epilepsy, muscular dystrophy, and hearing loss. The genotypic background of NS‐PME has expanded with pathogenic biallelic GOSR2 variants beyond the original homozygous founder mutation. Understanding the clinical spectrum and molecular mechanisms of GOSR2‐related diseases may facilitate more targeted treatment strategies as well as better‐informed phenotype predictions.