Identification of human D lactate dehydrogenase deficiency

Nat Commun. 2019 Apr 1;10(1):1477. doi: 10.1038/s41467-019-09458-6.

Glen R Monroe ¹ ², Albertien M van Eerde ¹ ², Federico Tessadori ¹ ² ³, Karen J Duran ¹ ², Sanne M C Savelberg ¹ ², Johanna C van Alfen ⁴, Paulien A Terhal ¹, Saskia N van der Crabben ⁵, Klaske D Lichtenbelt ¹, Sabine A Fuchs ⁵, Johan Gerrits ¹, Markus J van Roosmalen ¹ ², Koen L van Gassen ¹, Mirjam van Aalderen ¹, Bart G Koot ⁶, Marlies Oostendorp ⁷ ⁸, Marinus Duran ⁹, Gepke Visser ⁵, Tom J de Koning ¹⁰, Francesco Calì ¹¹, Paolo Bosco ¹¹, Karin Geleijns ¹², Monique G M de Sain-van der Velden ¹, Nine V Knoers ¹ ², Jeroen Bakkers ³ ¹³, Nanda M Verhoeven-Duif ¹ ², Gijs van Haaften ¹⁴ ¹⁵, Judith J Jans ¹ ²

Affiliations

1 Department of Genetics, University Medical Center Utrecht, Utrecht, 3584, CX, The Netherlands.
2 Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, 3584, CX, The Netherlands.
3 Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, 3584, CT, The Netherlands.
4 Bartiméus, Institute for the Visually Impaired, Doorn, 3940, AB, The Netherlands.
5 Department of Metabolic Diseases, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, 3584, EA, The Netherlands.
6 Department of Pediatric Gastroenterology and Nutrition, Academic Medical Center, Amsterdam, 1105, AZ, The Netherlands.
7 Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, 3584, CX, The Netherlands.
8 Laboratory of Clinical Chemistry, Deventer Hospital, Deventer, 7416, SE, The Netherlands.
9 Laboratory Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, 1105, AZ, The Netherlands.
10 Section of Metabolic Diseases, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, 9713, GZ, The Netherlands.
11 Oasi Research Institute-IRCCS, Troina, 94018, Italy.
12 Department of Child Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, 3584, CX, The Netherlands.
13 Department of Medical Physiology, University Medical Center Utrecht, Utrecht, 3584, CX, The Netherlands.
14 Department of Genetics, University Medical Center Utrecht, Utrecht, 3584, CX, The Netherlands. G.vanHaaften@umcutrecht.nl.
15 Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, 3584, CX, The Netherlands. G.vanHaaften@umcutrecht.nl.

PMID: 30931947 DOI: 10.1038/s41467-019-09458-6

Abstract

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.

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