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Hum Mol Genet. 2014 Sep 15;23(18):5009-16. doi: 10.1093/hmg/ddu218. Epub 2014 May 8.

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

Author information

1
Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Department of Pediatrics, Emma Children's Hospital, Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, Box 1498, New York, NY 10029, USA sander.houten@mssm.edu.
2
Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases.
3
Bioinformatics Laboratory, Clinical Epidemiology, Biostatistics and Bioinformatics and.
4
Bioinformatics Laboratory, Clinical Epidemiology, Biostatistics and Bioinformatics and Biosystems Data Analysis Group, University of Amsterdam, Science Park 904, 1098 XH Amsterdam, The Netherlands.
5
Department of Genome Analysis, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
6
Department of Pediatrics, Emma Children's Hospital.
7
Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.
8
Division of Genetics and Metabolism, Department of Pediatrics, University of North Carolina, Chapel Hill, NC, USA.
9
Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Department of Pediatrics, Emma Children's Hospital.

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.

PMID:
24847004
DOI:
10.1093/hmg/ddu218
[Indexed for MEDLINE]

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