Mitochondrial NADP(H) deficiency due to a mutation in NADK2 causes dienoyl-CoA reductase deficiency with hyperlysinemia.

Abstract

Dienoyl-CoA reductase (DECR) deficiency with hyperlysinemia is a rare disorder affecting the metabolism of polyunsaturated fatty acids and lysine. The molecular basis of this condition is currently unknown. We describe a new case with failure to thrive, developmental delay, lactic acidosis and severe encephalopathy suggestive of a mitochondrial disorder. Exome sequencing revealed a causal mutation in NADK2. NADK2 encodes the mitochondrial NAD kinase, which is crucial for NADP biosynthesis evidenced by decreased mitochondrial NADP(H) levels in patient fibroblasts. DECR and also the first step in lysine degradation are performed by NADP-dependent oxidoreductases explaining their in vivo deficiency. DECR activity was also deficient in lysates of patient fibroblasts and could only be rescued by transfecting patient cells with functional NADK2. Thus NADPH is not only crucial as a cosubstrate, but can also act as a molecular chaperone that activates and stabilizes enzymes. In addition to polyunsaturated fatty acid oxidation and lysine degradation, NADPH also plays a role in various other mitochondrial processes. We found decreased oxygen consumption and increased extracellular acidification in patient fibroblasts, which may explain why the disease course is consistent with clinical criteria for a mitochondrial disorder. We conclude that DECR deficiency with hyperlysinemia is caused by mitochondrial NADP(H) deficiency due to a mutation in NADK2.

• Authors: Sander M Houten, Simone Denis, Heleen Te Brinke, Aldo Jongejan, Antoine H C van Kampen, Edward J Bradley, Frank Baas, Raoul C M Hennekam, David S Millington, Sarah P Young, Dianne M Frazier, Muge Gucsavas-Calikoglu, Ronald J A Wanders
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 23 Issue 18 Pg. 5009-16 (Sep 15 2014) ISSN: 1460-2083 [Electronic] England
• PMID: 24847004 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Mitochondrial Proteins
• NADP
• Oxidoreductases Acting on CH-CH Group Donors
• 2,4-dienoyl-CoA reductase
• NADK2 protein, human
• Phosphotransferases (Alcohol Group Acceptor)

Topics

• Fibroblasts (metabolism)
• Humans
• Hyperlysinemias (genetics, physiopathology)
• Mitochondrial Proteins (genetics)
• Mutation
• NADP (deficiency)
• Oxidoreductases Acting on CH-CH Group Donors (deficiency)
• Phosphotransferases (Alcohol Group Acceptor) (genetics)
• Sequence Analysis, DNA
• Stress, Physiological