Contiguous gene deletion of ELOVL7, ERCC8 and NDUFAF2 in a patient with a fatal multisystem disorder.
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.
Janssen
Rolf J R J
RJ
Nijmegen Center for Mitochondrial Disorders at the Department of Pediatrics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Distelmaier
Felix
F
Smeets
Roel
R
Wijnhoven
Tessa
T
Østergaard
Elsebet
E
Jaspers
Nicolaas G J
NG
Raams
Anja
A
Kemp
Stephan
S
Rodenburg
Richard J T
RJ
Willems
Peter H M G
PH
van den Heuvel
Lambert P W J
LP
Smeitink
Jan A M
JA
Nijtmans
Leo G J
LG
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*
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