Identification, Characterization, and Treatment for a Taurine Transporter (SLC6A6) Variant Resulting in Taurine Deficiency and Pathologies in a Consanguineous Family.

Abstract

More than 200 Pakistani consanguineous families with multiple individuals having recessive visual impairments were evaluated by exome sequencing and genotyping. One of the families, F315, from the Kohat region of Pakistan contained 2 affected individuals with a homozygous deleterious variant Gly399Val (NM_003043.5:c.1196G>T) in the taurine transporter SLC6A6 (MIM:186854) which segregated with the phenotype of progressive retinal degeneration. Gly399 is highly conserved in vertebrates and molecular modeling suggests that the increased bulk of the valine substitution displaces Tyr138 which participates in substrate coordination and transport and is consistent with the hypomorphic variant exhibiting only ~15% of the transport capacity of the native protein as determined by taurine uptake analyses in HEK‐293 cells transiently or stably expressing SLC6A6 or the Gly399Val variant. The reduced function was attributed to a catalytic effect rather than plasma membrane levels and analysis of patient‐derived fibroblasts of affected individuals mirrored these findings. Affected individuals exhibited cone‐rod retinopathy and cardiomyopathy and remarkably taurine supplementation for 24 months resulted in resolution of the cardiomyopathy and clinical stabilization of the retinopathy.Support or Funding InformationProVisu foundation and ERC grant 219968 to S.E.A., and NIH grant DA027845 to L.K.H.