Abstract:
Brain dopamine-serotonin vesicular transport disease is an extremely rare disease caused by an autosomal recessive mutation in the SLC18A2 gene (solute carrier family 18 member A2), which encodes the VMAT2 (vesicular monoamine transporter 2) protein. VMAT2 is a membrane protein responsible for vesicular transport of monoamines, and disruption of this protein affects neurotransmission. This rare disease is a severe neurodevelopmental disorder affecting motor skills, development, and resulting in muscular hypotonia. The disease and Pro387Leu mutation was first identified in a consanguineous Saudi Arabian family, and recently a second case was identified in a New Zealand family, with strong evidence suggesting that a Pro237His mutation is causative. Transgenic Caenorhabditis elegans models were developed to investigate the effects of the New Zealand and Saudi Arabian mutations. Investigations into dopamine and serotonin related C. elegans phenotypes, including pharyngeal pumping, grazing, and egg-laying, showed that there is significant impairment of these processes when compared with a non-transgenic N2 strain, and a transgenic containing the non-mutated SLC18A2 gene. This analysis provides functional evidence that the Pro237His mutation within the New Zealand family is causative for their disease, and that the New Zealand mutation is more severe than the Saudi Arabian mutation. Finally, drug treatments (serotonin and the dopamine receptor agonist pramipexole) were investigated for their effect on the New Zealand transgenic, with serotonin successfully rescuing the pharyngeal pumping phenotype, showing that it is a strong candidate for further investigation as a treatment for this disease.
