title: Mutations of the mitochondrial holocytochrome c-type synthase in X-linked dominant microphthalmia with linear skin defects syndrome.
abstract: The microphthalmia with linear skin defects syndrome (MLS, or MIDAS) is an X-linked dominant male-lethal disorder almost invariably associated with segmental monosomy of the Xp22 region. In two female patients, from two families, with MLS and a normal karyotype, we identified heterozygous de novo point mutations--a missense mutation (p.R217C) and a nonsense mutation (p.R197X)--in the HCCS gene. HCCS encodes the mitochondrial holocytochrome c-type synthase that functions as heme lyase by covalently adding the prosthetic heme group to both apocytochrome c and c(1). We investigated a third family, displaying phenotypic variability, in which the mother and two of her daughters carry an 8.6-kb submicroscopic deletion encompassing part of the HCCS gene. Functional analysis demonstrates that both mutant proteins (R217C and Delta 197-268) were unable to complement a Saccharomyces cerevisiae mutant deficient for the HCCS orthologue Cyc3p, in contrast to wild-type HCCS. Moreover, ectopically expressed HCCS wild-type and the R217C mutant protein are targeted to mitochondria in CHO-K1 cells, whereas the C-terminal-truncated Delta 197-268 mutant failed to be sorted to mitochondria. Cytochrome c, the final product of holocytochrome c-type synthase activity, is implicated in both oxidative phosphorylation (OXPHOS) and apoptosis. We hypothesize that the inability of HCCS-deficient cells to undergo cytochrome c-mediated apoptosis may push cell death toward necrosis that gives rise to severe deterioration of the affected tissues. In summary, we suggest that disturbance of both OXPHOS and the balance between apoptosis and necrosis, as well as the X-inactivation pattern, may contribute to the variable phenotype observed in patients with MLS.
authors.affiliation: Institut fur Humangenetik, Universitatsklinikum Hamburg-Eppendorf, Butenfeld 42, Hamburg, Germany.
authors.forename: Isabella
authors.initials: I
authors.lastname: Wimplinger
authors.forename: Manuela
authors.initials: M
authors.lastname: Morleo
authors.forename: Georg
authors.initials: G
authors.lastname: Rosenberger
authors.forename: Daniela
authors.initials: D
authors.lastname: Iaconis
authors.forename: Ulrike
authors.initials: U
authors.lastname: Orth
authors.forename: Peter
authors.initials: P
authors.lastname: Meinecke
authors.forename: Israela
authors.initials: I
authors.lastname: Lerer
authors.forename: Andrea
authors.initials: A
authors.lastname: Ballabio
authors.forename: Andreas
authors.initials: A
authors.lastname: Gal
authors.forename: Brunella
authors.initials: B
authors.lastname: Franco
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kutsche
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D002648:Child; D002675:Child, Preschool; D006224:Cricetinae; D004247:DNA / Q000235:genetics; D005260:Female; D005799:Genes, Dominant; D050172:Genes, X-Linked; D005816:Genetic Complementation Test; D040181:Genetic Diseases, X-Linked / Q000201:enzymology* / Q000235:genetics*; D006239:Haplotypes; D020035:Holoenzymes / Q000235:genetics; D006801:Humans; D008190:Lyases / Q000235:genetics*; D008297:Male; D008850:Microphthalmos / Q000201:enzymology* / Q000235:genetics*; D008928:Mitochondria / Q000201:enzymology; D008969:Molecular Sequence Data; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017384:Sequence Deletion; D012868:Skin Abnormalities / Q000201:enzymology* / Q000235:genetics*; D013577:Syndrome; D049951:X Chromosome Inactivation
chemical_list: D020035:Holoenzymes; D004247:DNA; D008190:Lyases; C031581:cytochrome C synthetase