Hyperuricemia and gout caused by missense mutation in d-lactate dehydrogenase
Max Drabkin, Yuval Yogev, Lior Zeller, Raz Zarivach, Ran Zalk, Daniel Halperin, Ohad Wormser, Evgenia Gurevich, Daniel Landau, Rotem Kadir, Yonatan Perez, Ohad S. Birk
Max Drabkin, Yuval Yogev, Lior Zeller, Raz Zarivach, Ran Zalk, Daniel Halperin, Ohad Wormser, Evgenia Gurevich, Daniel Landau, Rotem Kadir, Yonatan Perez, Ohad S. Birk
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Concise Communication Genetics Metabolism

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

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.

Authors

Max Drabkin, Yuval Yogev, Lior Zeller, Raz Zarivach, Ran Zalk, Daniel Halperin, Ohad Wormser, Evgenia Gurevich, Daniel Landau, Rotem Kadir, Yonatan Perez, Ohad S. Birk

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Figure 2

LDHD mutation verification, conservation, and structural prediction.

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LDHD mutation verification, conservation, and structural prediction. (A...
(A) Sanger sequencing of a heterozygous obligatory carrier (II:3), a healthy family member (III:3), and an affected individual homozygous for the mutation (III:7). The c.1108C>T mutation is outlined by a black rectangle. (B) Alignment of LDHD ortholog sequences using Clustal Omega (https://www.ebi.ac.uk/Tools/msa/clustalo/). Identity and similarity were derived from the Basic Local Alignment Search Tool (BLAST) (https://blast.ncbi.nlm.nih.gov/Blast.cgi). The black box marks the highly conserved arginine residue altered by the c.1108C>T mutation. The symbols show conservation: asterisk indicates identical; colon indicates strongly similar; period indicates weakly similar; blank indicates no similarity. (C) Predicted structure of the human d-lactate dehydrogenase dimer, based on its closest structural homolog (putative dehydrogenase from Rhodopseudomonas palustris, Protein Data Bank [PDB] 3PM9 [https://www.rcsb.org/structure/3PM9], 30% protein sequence identity). The 2 monomers of d-lactate dehydrogenase are shown in light blue and dark green; FAD is represented as sticks in pink; the site of the p.R370W substitution is shown in orange; and the black arrow indicates the enzyme’s active site. (D) Zoom-in on the residues comprising the catalytic pocket of 3PM9 (yellow) and an overlay of the model for d-lactate dehydrogenase with its homologous residues (light blue). FAD is presented as sticks in pink; the site of the R370W substitution is shown in orange; the dashed lines indicate hydrogen bonds; nitrogen is labeled in blue; and oxygen is labeled in red.