TY - JOUR
T1 - Identification of human D lactate dehydrogenase deficiency
AU - Monroe, Glen R
AU - van Eerde, Albertien M
AU - Tessadori, Federico
AU - Duran, Karen J
AU - Savelberg, Sanne M C
AU - van Alfen, Johanna C
AU - Terhal, Paulien A
AU - van der Crabben, Saskia N
AU - Lichtenbelt, Klaske D
AU - Fuchs, Sabine A
AU - Gerrits, Johan
AU - van Roosmalen, Markus J
AU - van Gassen, Koen L
AU - van Aalderen, Mirjam
AU - Koot, Bart G
AU - Oostendorp, Marlies
AU - Duran, Marinus
AU - Visser, Gepke
AU - de Koning, Tom J
AU - Calì, Francesco
AU - Bosco, Paolo
AU - Geleijns, Karin
AU - de Sain-van der Velden, Monique G M
AU - Knoers, Nine V
AU - Bakkers, Jeroen
AU - Verhoeven-Duif, Nanda M
AU - van Haaften, Gijs
AU - Jans, Judith J
PY - 2019/4/1
Y1 - 2019/4/1
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-019-09458-6
DO - 10.1038/s41467-019-09458-6
M3 - Article
C2 - 30931947
SN - 2041-1723
VL - 10
SP - 1477
JO - Nature Communications
JF - Nature Communications
IS - 1
ER -