Human Molecular Genetics Advance Access originally published online on June 12, 2009
Human Molecular Genetics 2009 18(18):3365-3374; doi:10.1093/hmg/ddp276
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Contiguous gene deletion of ELOVL7, ERCC8 and NDUFAF2 in a patient with a fatal multisystem disorder
1 Nijmegen Center for Mitochondrial Disorders at the Department of Pediatrics, Laboratory of Pediatrics and Neurology and 2 Department of Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands, 3 Department of General Pediatrics, Heinrich-Heine-University, Düsseldorf, Germany, 4 Department of Clinical Genetics, National University Hospital Rigshospitalet, Copenhagen, Denmark, 5 Department of Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands and 6 Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
* To whom correspondence should be addressed. Tel: +31 243619470/15251; Fax: +31 243668532; Email: l.nijtmans{at}cukz.umcn.nl
Received April 8, 2009; Accepted June 8, 2009
Contiguous gene syndromes affecting the mitochondrial oxidative phosphorylation system have been rarely reported. Here, we describe a patient with apparent mitochondrial encephalomyopathy accompanied by several unusual features, including dysmorphism and hepatopathy, caused by a homozygous triple gene deletion on chromosome 5. The deletion encompassed the NDUFAF2, ERCC8 and ELOVL7 genes, encoding complex I assembly factor 2 (also known as human B17.2L), a protein of the transcription-coupled nucleotide excision repair (TC-NER) machinery, and a putative elongase of very long-chain fatty acid synthesis, respectively. Detailed evaluation of cultured skin fibroblasts revealed disturbed complex I assembly, depolarization of the mitochondrial membrane, elevated cellular NAD(P)H level, increased superoxide production and defective TC-NER. ELOVL7 mRNA was not detectable in these cells and no alterations in fatty acid synthesis were found. By means of baculoviral complementation we were able to restore the aberrations, thereby establishing causative links between genotype and cell-physiological phenotype. This first chromosomal microdeletion illustrates that beside primary defects in mitochondrial genes also additional genes possibly contribute to the disease phenotype, providing an additional explanation for the broad clinical symptoms associated with these disorders.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.