Identification of human D lactate dehydrogenase deficiency

• Published in: Nature communications Vol. 10; no. 1; p. 1477
• Main Authors: Monroe, Glen R., van Eerde, Albertien M., Tessadori, Federico, Duran, Karen J., Savelberg, Sanne M. C., van Alfen, Johanna C., Terhal, Paulien A., van der Crabben, Saskia N., Lichtenbelt, Klaske D., Fuchs, Sabine A., Gerrits, Johan, van Roosmalen, Markus J., van Gassen, Koen L., van Aalderen, Mirjam, Koot, Bart G., Oostendorp, Marlies, Duran, Marinus, Visser, Gepke, de Koning, Tom J., Calì, Francesco, Bosco, Paolo, Geleijns, Karin, de Sain-van der Velden, Monique G. M., Knoers, Nine V., Bakkers, Jeroen, Verhoeven-Duif, Nanda M., van Haaften, Gijs, Jans, Judith J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 45; 45/23; 631/1647/296; 631/1647/514; 631/208; 631/45/147; 631/45/320; 64; 64/116; 82/58; Acidosis; Acidosis, Lactic - diagnosis; Acidosis, Lactic - genetics; Adult; Animals; Consanguinity; Dehydrogenase; Dehydrogenases; Diagnosis, Differential; Differential diagnosis; Excretion; Homozygote; Human behavior; Humanities and Social Sciences; Humans; Infant; Intestine; L-Lactate dehydrogenase; Lactate dehydrogenase; Lactate Dehydrogenases - deficiency; Lactate Dehydrogenases - genetics; Lactic acid; Lactic Acid - metabolism; Lactic acidosis; Loss of Function Mutation; Male; Metabolism; multidisciplinary; Patients; Science; Science (multidisciplinary); Short bowel syndrome; Short Bowel Syndrome - metabolism; Spasms, Infantile - diagnosis; Spasms, Infantile - genetics; Zebrafish
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-09458-6

Phenotypic and biochemical categorization of humans with detrimental variants can provide valuable information on gene function. We illustrate this with the identification of two different homozygous variants resulting in enzymatic loss-of-function in LDHD , encoding lactate dehydrogenase D, in two unrelated patients with elevated D-lactate urinary excretion and plasma concentrations. We establish the role of LDHD by demonstrating that LDHD loss-of-function in zebrafish results in increased concentrations of D-lactate. D-lactate levels are rescued by wildtype LDHD but not by patients’ variant LDHD , confirming these variants’ loss-of-function effect. This work provides the first in vivo evidence that LDHD is responsible for human D-lactate metabolism. This broadens the differential diagnosis of D-lactic acidosis, an increasingly recognized complication of short bowel syndrome with unpredictable onset and severity. With the expanding incidence of intestinal resection for disease or obesity, the elucidation of this metabolic pathway may have relevance for those patients with D-lactic acidosis. D-lactic acidosis typically occurs in the context of short bowel syndrome; excess D-lactate is produced by intestinal bacteria. Here, the authors identify two point mutations in the human lactate dehydrogenase D (LDHD) gene that cause enzymatic loss of function and are associated with elevated plasma D-lactate.