Nature communications · 2019
Identification of human D lactate dehydrogenase deficiency.
Клинический случайСтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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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
Аннотация
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.