title: Contiguous gene deletion of ELOVL7, ERCC8 and NDUFAF2 in a patient with a fatal multisystem disorder.
abstract: 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.
authors.affiliation: Nijmegen Center for Mitochondrial Disorders at the Department of Pediatrics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Rolf J R J
authors.initials: RJ
authors.lastname: Janssen
authors.forename: Felix
authors.initials: F
authors.lastname: Distelmaier
authors.forename: Roel
authors.initials: R
authors.lastname: Smeets
authors.forename: Tessa
authors.initials: T
authors.lastname: Wijnhoven
authors.forename: Elsebet
authors.initials: E
authors.lastname: Østergaard
authors.forename: Nicolaas G J
authors.initials: NG
authors.lastname: Jaspers
authors.forename: Anja
authors.initials: A
authors.lastname: Raams
authors.forename: Stephan
authors.initials: S
authors.lastname: Kemp
authors.forename: Richard J T
authors.initials: RJ
authors.lastname: Rodenburg
authors.forename: Peter H M G
authors.initials: PH
authors.lastname: Willems
authors.forename: Lambert P W J
authors.initials: LP
authors.lastname: van den Heuvel
authors.forename: Jan A M
authors.initials: JA
authors.lastname: Smeitink
authors.forename: Leo G J
authors.initials: LG
authors.lastname: Nijtmans
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000378:metabolism; D000123:Acetyltransferases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D017809:Fatal Outcome; D000081031:Fatty Acid Elongases; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007231:Infant, Newborn; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics*; D018832:Molecular Chaperones / Q000235:genetics*; D009154:Mutation; D010084:Oxidation-Reduction; D010766:Phosphorylation; D011485:Protein Binding; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C000630957:ELOVL7 protein, human; C095472:ERCC8 protein, human; D005227:Fatty Acids; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; C501824:NDUFAF2 protein, human; D014157:Transcription Factors; D000123:Acetyltransferases; D000081031:Fatty Acid Elongases; D045643:DNA Repair Enzymes