The VAMP1 gene encodes synaptobrevin-1, an integral membrane protein involved in vesicle fusion and neuronal exocytosis. The protein is tethered to the synaptic vesicle membrane and forms a SNARE complex with syntaxin and SNAP25 on the plasma membrane, thereby helping in the docking and/or fusion of synaptic vesicles with the presynaptic membrane.
The gene has been implicated in Spastic Ataxia 1, Autosomal Dominant (SPAX1), a progressive neurodegenerative disorder characterized by spastic paraplegia, dysarthria and impaired ocular movements.
The gene is located on the short arm of chromosome 12. It spans a length of 8.7 kb of DNA and its coding sequence is spread across 5 exons. The gene encodes a 12.9 kDa protein product consisting of 118 amino acids. Several additional tissue-specific isoforms of the VAMP1 protein exist due to alternatively spliced transcript variants. The gene is found to be expressed mainly in the nervous system, skeletal muscle and adipose tissue. Heterozygous mutations in the gene have been implicated in Spastic Ataxia 1. However, recent studies have also found instances of SPAX1 affected individuals with homozygous VAMP1 mutations.
Monies et al. (2017) described the findings of 1000 diagnostic panels and exomes carried out at a next generation sequencing lab in Saudi Arabia. One patient, an 8-month-old male, suffered from an atrial septal defect, fine/gross motor delay, hypotonia, muscle weakness, contractures, pneumonia congenital myopathy and congenital muscular dystrophy. WES was used to identify a homozygous mutation (c.128_129del, p.E43fs) in exon 2 of the patient’s VAMP1 gene. Another patient, a 2-year-old female presented with congenital hypotonia, rigid spine, myopathic facies and normal CK levels. Her parents were not related and her family history was negative for this phenotype. WES helped uncover a homozygous c.129+1G>A mutation in exon 2 of the patient’s VAMP1 gene. As VAMP1 is generally implicated in autosomal dominant SPAX1, these recessive mutations were a unique finding. They were attributed to enhanced autozygosity and were noted to help our understanding of the molecular pathogenesis of the dominant counterpart.