Hyperuricemia and gout caused by missense mutation in D-lactate dehydrogenase

Through genetic studies we present a novel molecular pathway for Gout. Gout is caused by deposition of monosodium urate crystals in joints when plasma uric acid levels are chronically elevated beyond saturation threshold, mostly due to renal under-excretion of uric acid. While molecular pathways of this under-excretion have been elucidated, its etiology remains mostly unknown. Studying a consanguineous kindred, we demonstrate that gout can be caused by a mutation in LDHD within the putative catalytic site of the encoded D-lactate dehydrogenase, resulting in augmented blood levels of D-lactate, a stereoisomer of L-lactate, normally present in human blood in miniscule amounts. Consequent excessive renal secretion of D-lactate in exchange for uric acid reabsorption culminated in hyperuricemia and gout. We showed that LDHD expression is enriched in tissues with high metabolic rate and abundant mitochondria, and that D-lactate dehydrogenase resides in the mitochondria of cells overexpressing the human LDHD gene. Notably, the p.R370W mutation had no effect on protein localization. In line with the human phenotype, injection of D-lactate to naïve mice resulted in hyperuricemia. Thus, hyperuricemia and gout can result from accumulation of metabolites whose renal excretion is coupled to uric acid reabsorption.