Expanding the Phenotype and Genetic Defects Associated with the GOSR2 Gene

Abstract

Background: The homozygous missense mutation c. 430G>T (p.G144W) in the GOSR2 gene has been repeatedly shown to cause progressive myoclonus epilepsy/ataxia. Thus far, no other disease associated GOSR2 mutation has been reported. Methods: From epilepsy, movement disorder and genetic clinics 43 patients suffering from progressive myoclonus epilepsy/ataxia were screened for defects in GOSR2, SCARB2 and CSTB. Results: A 61-year-old female patient suffering from progressive myoclonus epilepsy was found to be compound heterozygous for the known c.430G>T and a novel c.491_493delAGA (p.K164del) GOSR2 mutation. This is so far the oldest GOSR2 patient and her disease course seems overall milder. Conclusions: This finding further highlights the GOSR2 gene as a cause of progressive myoclonus epilepsy and expands the genotype for a potentially weaker disease allele.Progressive myoclonus epilepsies (PMEs) or ataxias are a group of neurological syndromes characterized by myoclonus, ataxia, epilepsy, and often cognitive decline, which worsen over time. 1 PMEs can clinically be subdivided depending on whether cognitive decline is a prominent feature, 1 and mode of inheritance can be a further clue toward the causative gene. Four genes are known to be associated with autosomal-recessive PME with largely preserved intellect: CSTB (MIM 601145) 2 ; SCARB2 (MIM 602257) 3,4 ; PRICKLE1 (MIM 608500) 5 ; and GOSR2 (MIM 604027). 6 Recently, a heterozygous de novo mutation in KCNC1 (MIM 176258) has been shown to cause the same phenotype. 7 The most prominent PME with largely preserved cognition is Unverricht-Lundborg disease (ULD; MIM 254800) resulting from mutations in the CSTB gene. 2 Mutations in Golgi SNAP receptor complex member 2 (GOSR2) have been shown to cause an ULD-like phenotype. 6,8,9 However, this disease usually onsets earlier than ULD, around age 2, with myoclonus and ataxia. Frequently, generalized tonic-clonic seizures then develop. Owing to rapid progression of action myoclonus and ataxia, patients are often left wheelchair bound already in their first or second decade. Thus far, all 17 reported patients with GOSR2-mediated PME have been shown to carry the same homozygous c.430G>T (p.G144W) mutation, the result of a founder effect. 6,8,9 No other GOSR2 mutation has thus far been shown to be associated with PME. MethodsWe assembled a cohort of 43 single patients or family probands showing a clinical presentation suggestive for progressive myoclonus epilepsy/ataxia syndrome. Patients were negative for mutations in ATN1, mitochondrial A8344G, and A3243G. The study was approved by the local ethical board, and informed consent was given by all patients. All 12 scavenger receptor class B, member 2 (SCARB2) exons and GOSR2 c.430G>T were screened by Sanger sequencing. ResultsWe report here on the analysis of a series of 43 PME families/ patients. Twelve patients were found to have CSTB mutations. Sequencing the remaining 31 probands found no SCARB2

GOSR2: a progressive myoclonus epilepsy gene

“…The progression of the S113 GOSR2: a progressive myoclonus epilepsy gene disease showed a relentless decline; patients became wheelchair-bound (at a mean age of 13 years) and four died during their third or fourth decade of life. An additional patient with PME caused by mutation in GOSR2 has been reported by Praschberger et al (2015). This patient was a 61-year-old female presenting with a PME phenotype and was found to be compound heterozygous for two GOSR2 mutations; the known c.430G>T, Gly144Trp mutation and a novel c.491_493delAGA (p.Lys164del) mutation.…”

“…Brain magnetic resonance imaging studies have displayed essentially normal findings or generalized cerebral and cerebellar atrophy (Boissé Lomax et al ., ; Prachschberger et al ., ). Elevation of serum creatine kinase levels (median: 734 IU), in the context of normal muscle biopsies, was reported for all patients in the study of Boissé Lomax et al .…”

“…An additional patient with PME caused by mutation in GOSR2 has been reported by Praschberger et al . (). This patient was a 61‐year‐old female presenting with a PME phenotype and was found to be compound heterozygous for two GOSR2 mutations; the known c.430G>T, Gly144Trp mutation and a novel c.491_493delAGA (p.Lys164del) mutation.…”

Mutations in Membrin/GOSR2reveal stringent secretory pathway demands of dendritic growth and synaptic integrity

“…Homozygous missense (G144W: layer -3) or compound heterozygous missense and deletion mutations (G144W & K164del: between layer +2 and +3) in Membrin's SNARE motif have recently been shown to cause the severe neurological syndrome progressive myoclonus epilepsy (PME) (Corbett et al, 2011;Praschberger et al, 2015). Patients with this form of PME, termed GOSR2-PME, typically present with ataxia around age three, followed by cortical myoclonus and generalized tonic-clonic seizures.…”

“…Correspondingly, marked neurodegeneration as an underlying primary cause has not been reported (Boissé Lomax et al, 2013;Corbett et al, 2011;Praschberger et al, 2015;van Egmond et al, 2015;2014). Given the critical role of Membrin in ER-to-Golgi trafficking and its fundamental importance in every cell of the human body, it is unclear why Membrin mutations specifically result in nervous system dysfunction and do not cause symptoms in other organs.…”