Identification of human D lactate dehydrogenase deficiency

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

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish
Article number1477
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - Dec 1 2019

Fingerprint

Forensic Anthropology
lactates
dehydrogenases
Lactic Acid
acidosis
Lactic Acidosis
Short Bowel Syndrome
Intestinal Diseases
obesity
Zebrafish
Metabolic Networks and Pathways
excretion
Metabolism
metabolism
Differential Diagnosis
Obesity
Genes
genes
Plasmas
coding

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Monroe, G. R., van Eerde, A. M., Tessadori, F., Duran, K. J., Savelberg, S. M. C., van Alfen, J. C., ... Jans, J. J. (2019). Identification of human D lactate dehydrogenase deficiency. Nature Communications, 10(1), [1477]. https://doi.org/10.1038/s41467-019-09458-6

Identification of human D lactate dehydrogenase deficiency. / 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.

In: Nature Communications, Vol. 10, No. 1, 1477, 01.12.2019.

Research output: Contribution to journalArticle

Monroe, GR, van Eerde, AM, Tessadori, F, Duran, KJ, Savelberg, SMC, van Alfen, JC, Terhal, PA, van der Crabben, SN, Lichtenbelt, KD, Fuchs, SA, Gerrits, J, van Roosmalen, MJ, van Gassen, KL, van Aalderen, M, Koot, BG, Oostendorp, M, Duran, M, Visser, G, de Koning, TJ, Calì, F, Bosco, P, Geleijns, K, de Sain-van der Velden, MGM, Knoers, NV, Bakkers, J, Verhoeven-Duif, NM, van Haaften, G & Jans, JJ 2019, 'Identification of human D lactate dehydrogenase deficiency', Nature Communications, vol. 10, no. 1, 1477. https://doi.org/10.1038/s41467-019-09458-6
Monroe GR, van Eerde AM, Tessadori F, Duran KJ, Savelberg SMC, van Alfen JC et al. Identification of human D lactate dehydrogenase deficiency. Nature Communications. 2019 Dec 1;10(1). 1477. https://doi.org/10.1038/s41467-019-09458-6
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. / Identification of human D lactate dehydrogenase deficiency. In: Nature Communications. 2019 ; Vol. 10, No. 1.
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AU - van Alfen, Johanna C.

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