Novel synaptobrevin‐1 mutation causes fatal congenital myasthenic syndrome

Abstract

ObjectiveTo identify the molecular basis and elucidate the pathogenesis of a fatal congenital myasthenic syndrome.MethodsWe performed clinical electrophysiology studies, exome and Sanger sequencing, and analyzed functional consequences of the identified mutation.ResultsClinical electrophysiology studies of the patient revealed several‐fold potentiation of the evoked muscle action potential by high frequency nerve stimulation pointing to a presynaptic defect. Exome sequencing identified a homozygous c.340delA frameshift mutation in synaptobrevin 1 (SYB1), one of the three SNARE proteins essential for synaptic vesicle exocytosis. Analysis of both human spinal cord gray matter and normal human muscle revealed expression of the SYB1A and SYB1D isoforms, predicting expression of one or both isoforms in the motor nerve terminal. The identified mutation elongates the intravesicular C‐terminus of the A isoform from 5 to 71, and of the D isoform from 4 to 31 residues. Transfection of either mutant isoform into bovine chromaffin cells markedly reduces depolarization‐evoked exocytosis, and transfection of either mutant isoform into HEK cells significantly decreases expression of either mutant compared to wild type.InterpretationThe mutation is pathogenic because elongation of the intravesicular C‐terminus of the A and D isoforms increases the energy required to move their C‐terminus into the synaptic vesicle membrane, a key step for fusion of the synaptic vesicle with the presynaptic membrane, and because it is predicted to reduce expression of either isoform in the nerve terminal.

VAMP1-Related Congenital Myasthenic Syndrome: A Case Report and Literature Review

“…1 (A-C only eight types of allelic variants in the VAMP1 gene have been reported in 12 cases of CMS-25 from Brazil, Israel, Kuwait, Saudi Arabia, Lebanon, and India (►Table 1). 4,6,[8][9][10][11][12] Our case displayed common features with other CMS-25 cases associated with homozygous VAMP1 gene mutations, including axial hypotonia, muscle weakness, motor developmental delay, myopathic face, strabismus, feeding difficulties, malnutrition, respiratory distress and infections, kyphoscoliosis, and joint contractures. Notably, the patient also had less commonly reported features such as ptosis, seizures, joint laxity, and reduced fetal movements.…”

“…To date, only 3 of the 12 cases of VAMP1-related CMS-25 have undergone brain MRI, and all were normal. 4,6 The etiology of the focal cerebellar hypoplasia identified in our patient remains uncertain, whether it is a part of the primary disease or an incidental finding. However, Elferink et al 13 demonstrated the expression of VAMP1 in both the brain and spinal cord.…”

The Increasing Genetic and Phenotypical Diversity of Congenital Myasthenic Syndromes

“…In CMS subtypes in which the primary defect results in impairment of ACh release, RNS performed at high frequency for a prolonged period (e.g., 10Hz for 5 minutes) results in an opposing effect and an increment in CMAP amplitude is observed. [24][25][26] This is similar to the effect seen in the immune-mediated Lambert-Eaton myasthenic syndrome (LEMS). 27 In other presynaptic CMS subtypes in which the defect is not in impairment of ACh release, but in its synthesis in the presynaptic nerve terminal (e.g., CHAT-CMS), often no decrement is detected at low-frequency (3 Hz) RNS, and it is not until the pool of synaptic vesicles has been exhausted that any decrement is observed.…”

Congenital myasthenic syndromes

“…Another possibility to classify CMS is the type of mutation such as point mutations (missense or truncating (frameshift, splice site, nonsense)), deletions, duplications, indels, or insertions. According to the long-term course, CMS may be classified as progressive, fluctuating, or regressive [7].…”

“…SYB1 encodes for the SNARE protein synaptobrevin, which is essential for synaptic vesicle exocytosis [7]. Mutations in SYB1 have been reported in a single patient with CMS [7]. The female presented at birth with marked hypotonia and feeding difficulties [7].…”