2. Academic Validation
  3. Hyperuricemia and gout caused by missense mutation in d-lactate dehydrogenase

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

  • J Clin Invest. 2019 Dec 2;129(12):5163-5168. doi: 10.1172/JCI129057.
Max Drabkin 1,  Yuval Yogev 1,  Lior Zeller 2,  Raz Zarivach 3 4,  Ran Zalk 4,  Daniel Halperin 1,  Ohad Wormser 1,  Evgenia Gurevich 5,  Daniel Landau 6,  Rotem Kadir 1,  Yonatan Perez 1,  Ohad S Birk 1 7
Affiliations

Affiliations

  • 1 The Morris Kahn Laboratory of Human Genetics at the Faculty of Health Sciences, National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
  • 2 Division of Internal Medicine, Soroka University Medical Center, Beer-Sheva, Israel.
  • 3 Department of Life Sciences and.
  • 4 National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
  • 5 Rahat Children's Health Center, Clalit Health Services, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
  • 6 Department of Pediatrics B and Pediatric Nephrology Unit, Schneider Children's Medical Center of Israel, Petach Tikva and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • 7 Genetics Institute, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
PMID: 31638601 DOI: 10.1172/JCI129057
Abstract

Gout is caused by deposition of monosodium urate crystals in joints when plasma uric acid levels are chronically elevated beyond the saturation threshold, mostly due to renal underexcretion of uric acid. Although molecular pathways of this underexcretion have been elucidated, its etiology remains mostly unknown. 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, which is 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 a 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 into naive mice resulted in hyperuricemia. Thus, hyperuricemia and gout can result from the accumulation of metabolites whose renal excretion is coupled to uric acid reabsorption.

Keywords

Arthritis; Diabetes; Genetic diseases; Genetics; Metabolism.

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