Mutation of the brain-specific L-proline transporter (SLC6A7) in infantile-onset hyperkinesia with epilepsy and neurodevelopmental delay

ABSTRACT
Many of the solute carrier family 6 (SLC6) transporters have fundamental roles in neurotransmitter homeostasis within the central nervous system. This is clearly exemplified in human disease, where loss-of-function mutations in genes encoding specific SLC6 proteins lead to severe, early onset neurological disorders. We report the identification of a homozygous missense mutation (G396S) in the brain-specific L-proline transporter gene, SLC6A7, in children with severely delayed neurodevelopment and a hyperkinetic movement disorder. The L-proline transporter (PROT) is exclusively expressed in the brain, specifically in a subpopulation of glutamatergic neurons, where it regulates the reuptake of L-proline into presynaptic terminals. Structural homology modelling predicts that G396S negatively impacts substrate recognition and stabilisation of unwound transmembrane helices. In comparison to wild-type PROT, the G396S mutant shows reduced cell-surface expression of the mature transporter with subsequent decrease in proline transport activity. Morpholino knockdown of slc6a7 in zebrafish also results in severe developmental delay and fragile motor neuron morphology. Our findings highlight a new neurological syndrome associated with SLC6A7 defects and underline a significant role for PROT in normal human neurodevelopment.