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Am J Hum Genet. 2015 Nov 5;97(5):761-8. doi: 10.1016/j.ajhg.2015.09.013. Epub 2015 Oct 29.

Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26.

Author information

1
Division of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan.
2
Max Planck Institute Biology of Ageing - Karolinska Institutet Laboratory, Division of Metabolic Diseases, Department of Laboratory Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden.
3
Department of Medical Genetics, Faculty of Medicine and Health Sciences, Antwerp University Hospital, University of Antwerp, Antwerp 2650, Belgium.
4
Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Via Edoardo Orabona 4, 70125 Bari, Italy.
5
Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Via Edoardo Orabona 4, 70125 Bari, Italy; Department of Sciences, University of Basilicata, Via Ateneo Lucano 10, 85100 Potenza, Italy.
6
Division of Translational Research, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan.
7
Centre for Inherited Metabolic Diseases, Karolinska University Hospital, 171 76 Stockholm, Sweden; Science for Life Laboratory and Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden.
8
Department of Metabolism, Chiba Children's Hospital, 579-1 Heta-cho, Midori, Chiba 266-0007, Japan.
9
Centre for Inherited Metabolic Diseases, Karolinska University Hospital, 171 76 Stockholm, Sweden; Department of Laboratory Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden.
10
Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany.
11
Department of Pathology, Karolinska University Hospital, 171 77 Stockholm, Sweden.
12
Paola Children's Hospital, ZNA Middelheim, Antwerp 2650, Belgium.
13
Department of Pediatrics, Saitama Medical University, 38 Morohongo Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan.
14
Department of Medical Genetics, Faculty of Medicine and Health Sciences, Antwerp University Hospital, University of Antwerp, Antwerp 2650, Belgium; Department of Genetics, Radboud University Medical Center, Nijmegen, 6525 GA, the Netherlands.
15
Max Planck Institute Biology of Ageing - Karolinska Institutet Laboratory, Division of Metabolic Diseases, Department of Laboratory Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, 171 76 Stockholm, Sweden.
16
Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Via Edoardo Orabona 4, 70125 Bari, Italy. Electronic address: ferdinando.palmieri@uniba.it.
17
Max Planck Institute Biology of Ageing - Karolinska Institutet Laboratory, Division of Metabolic Diseases, Department of Laboratory Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, 171 76 Stockholm, Sweden. Electronic address: anna.wredenberg@ki.se.
18
Division of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan; Division of Translational Research, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan.
19
Max Planck Institute Biology of Ageing - Karolinska Institutet Laboratory, Division of Metabolic Diseases, Department of Laboratory Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, 171 76 Stockholm, Sweden; Science for Life Laboratory and Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden.

Abstract

S-adenosylmethionine (SAM) is the predominant methyl group donor and has a large spectrum of target substrates. As such, it is essential for nearly all biological methylation reactions. SAM is synthesized by methionine adenosyltransferase from methionine and ATP in the cytoplasm and subsequently distributed throughout the different cellular compartments, including mitochondria, where methylation is mostly required for nucleic-acid modifications and respiratory-chain function. We report a syndrome in three families affected by reduced intra-mitochondrial methylation caused by recessive mutations in the gene encoding the only known mitochondrial SAM transporter, SLC25A26. Clinical findings ranged from neonatal mortality resulting from respiratory insufficiency and hydrops to childhood acute episodes of cardiopulmonary failure and slowly progressive muscle weakness. We show that SLC25A26 mutations cause various mitochondrial defects, including those affecting RNA stability, protein modification, mitochondrial translation, and the biosynthesis of CoQ10 and lipoic acid.

KEYWORDS:

S-adenosylmethionine; SAM; SLC25A26; methylation; mitochondria; mitochondrial dysfunction

PMID:
26522469
PMCID:
PMC4667130
DOI:
10.1016/j.ajhg.2015.09.013
[Indexed for MEDLINE]
Free PMC Article

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