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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. and Fuchs, Sabine A. , et al. (2019) In Nature Communications 10(1).
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... (More)

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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publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
10
issue
1
article number
1477
publisher
Nature Publishing Group
external identifiers
  • scopus:85063734330
  • pmid:30931947
ISSN
2041-1723
DOI
10.1038/s41467-019-09458-6
language
English
LU publication?
no
id
302748f7-9697-4cc6-8c25-121df04236ed
date added to LUP
2020-02-11 12:13:06
date last changed
2024-06-12 09:34:15
@article{302748f7-9697-4cc6-8c25-121df04236ed,
  abstract     = {{<p>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.</p>}},
  author       = {{Monroe, Glen R. and van Eerde, Albertien M. and Tessadori, Federico and Duran, Karen J. and Savelberg, Sanne M.C. and van Alfen, Johanna C. and Terhal, Paulien A. and van der Crabben, Saskia N. and Lichtenbelt, Klaske D. and Fuchs, Sabine A. and Gerrits, Johan and van Roosmalen, Markus J. and van Gassen, Koen L. and van Aalderen, Mirjam and Koot, Bart G. and Oostendorp, Marlies and Duran, Marinus and Visser, Gepke and de Koning, Tom J. and Calì, Francesco and Bosco, Paolo and Geleijns, Karin and de Sain-van der Velden, Monique G.M. and Knoers, Nine V. and Bakkers, Jeroen and Verhoeven-Duif, Nanda M. and van Haaften, Gijs and Jans, Judith J.}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Identification of human D lactate dehydrogenase deficiency}},
  url          = {{http://dx.doi.org/10.1038/s41467-019-09458-6}},
  doi          = {{10.1038/s41467-019-09458-6}},
  volume       = {{10}},
  year         = {{2019}},
}