GOSR2 – Progressive Myoclonus Epilepsy Type 6

In a consanguineous Afrikaans family, three individuals homozygous for the founder GOSR2 missense variant c.430G>T (p.Gly144Trp) presented in early childhood with ataxia, tremor, gait difficulties, and myoclonic and generalized tonic-clonic seizures fulfilling the phenotype of North Sea progressive myoclonic epilepsy type 6 (PMID:30838261). Deep brain stimulation of the caudal zona incerta in all three cases led to sustained reduction in seizure frequency and involuntary movements over long-term follow-up.

Functional assays in yeast and Drosophila models carrying the orthologous p.Gly144Trp mutation demonstrate a partial loss-of-function mechanism. Yeast expressing Bos1 p.Gly176Trp showed impaired growth and reduced SNARE complex activity, while Drosophila models exhibited dendritic growth deficits, presynaptic cytoskeletal fragmentation, and hyperactive neurotransmission mirroring human pathology (PMID:28982678; PMID:28978487).

Key take-home: Biallelic GOSR2 missense variants cause autosomal recessive North Sea PME type 6 via a partial loss-of-function SNARE mechanism, informing genetic diagnosis and potential neuromodulatory therapies.

References

• Movement Disorders Clinical Practice • 2017 • Deep Brain Stimulation in Three Related Cases of North Sea Progressive Myoclonic Epilepsy from South Africa. PMID:30838261
• Disease Models & Mechanisms • 2017 • Functional assays for the assessment of the pathogenicity of variants of GOSR2, an ER-to-Golgi SNARE involved in progressive myoclonus epilepsies. PMID:28982678
• Cell Reports • 2017 • Mutations in Membrin/GOSR2 Reveal Stringent Secretory Pathway Demands of Dendritic Growth and Synaptic Integrity. PMID:28978487

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