Contiguous gene deletion of ELOVL7, ERCC8 and NDUFAF2 in a patient with a fatal multisystem disorder

• Published in: Human molecular genetics 2009-09, Vol.18 (18), p.3365-3374
• Main Authors: Janssen, Rolf J.R.J., Distelmaier, Felix, Smeets, Roel, Wijnhoven, Tessa, Østergaard, Elsebet, Jaspers, Nicolaas G.J., Raams, Anja, Kemp, Stephan, Rodenburg, Richard J.T., Willems, Peter H.M.G., van den Heuvel, Lambert P.W.J., Smeitink, Jan A.M., Nijtmans, Leo G.J.
• Format: Article
• Language: English
• Subjects: Abnormalities, Multiple - genetics; Abnormalities, Multiple - metabolism; Acetyltransferases - genetics; Biological and medical sciences; DNA Repair Enzymes - genetics; Fatal Outcome; Fatty Acids - metabolism; Female; Fundamental and applied biological sciences. Psychology; Gene Deletion; Genetics of eukaryotes. Biological and molecular evolution; Humans; Infant, Newborn; Mitochondria - metabolism; Mitochondrial Proteins - genetics; Molecular and cellular biology; Molecular Chaperones - genetics; Mutation; Oxidation-Reduction; Phosphorylation; Protein Binding; Transcription Factors - genetics
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddp276

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.