Cytochrome c-type heme lyase is an enzyme that in humans is encoded by the HCCSgene on chromosome X.[5]
Structure
The HCCS gene is located on the Xp22 region of chromosome X and encodes a protein that is ~30 kDa in size. The HCCS protein is localized to the inner mitochondrial membrane and is expressed in multiple tissue including prominently in the cardiovascular system and the central nervous system.[6]
Function
The HCCS protein functions as a lyase to covalently attach the heme group to the apoprotein of cytochrome c on the inner mitochondrial membrane of the mitochondrion.[7] The heme group is required for cytochrome c to transport electrons from complex III to complex IV of the electron transport chain during respiration. Heme attachment to cytochrome c takes place in the intermembrane space and requires conserved heme-interacting residues on HCCS on one of the two heme-binding domains on HCCS, including His154.[8] The HCCS protein may function to regulate mitochondrial lipid and total mitochondrial mass in response to mitochondrial dysfunctions.[9]
Clinical significance
Mutations in the HCCS gene cause microphthalmia with linear skin defects (MLS) syndrome,[10] also known as MIDAS syndrome, microphthalmia, syndromic 7 (MCOPS7), or microphthalmia, dermal aplasia, and sclerocornea.[11][12] MLS is a rare X-linked dominant male-lethal disease characterized by unilateral or bilateral microphthalmia and linear skin defects in affected females, and in utero lethality for affected males.[11]
References
^ a b cGRCh38: Ensembl release 89: ENSG00000004961 – Ensembl, May 2017
^ a b cGRCm38: Ensembl release 89: ENSMUSG00000031352 – Ensembl, May 2017
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Entrez Gene: HCCS holocytochrome c synthase (cytochrome c heme-lyase)".
^"Search results < Expression Atlas < EMBL-EBI".
^Babbitt SE, San Francisco B, Mendez DL, Lukat-Rodgers GS, Rodgers KR, Bretsnyder EC, Kranz RG (2014). "Mechanisms of mitochondrial holocytochrome c synthase and the key roles played by cysteines and histidine of the heme attachment site, Cys-XX-Cys-His". J. Biol. Chem. 289 (42): 28795–807. doi:10.1074/jbc.M114.593509. PMC4200240. PMID 25170082.
^Babbitt SE, San Francisco B, Bretsnyder EC, Kranz RG (2014). "Conserved residues of the human mitochondrial holocytochrome c synthase mediate interactions with heme". Biochemistry. 53 (32): 5261–71. doi:10.1021/bi500704p. PMC4139152. PMID 25054239.
^Nakashima-Kamimura N, Asoh S, Ishibashi Y, Mukai Y, Shidara Y, Oda H, Munakata K, Goto Y, Ohta S (2005). "MIDAS/GPP34, a nuclear gene product, regulates total mitochondrial mass in response to mitochondrial dysfunction". J. Cell Sci. 118 (Pt 22): 5357–67. doi:10.1242/jcs.02645. PMID 16263763.
^Wimplinger I, Morleo M, Rosenberger G, Iaconis D, Orth U, Meinecke P, Lerer I, Ballabio A, Gal A, Franco B, Kutsche K (2006). "Mutations of the mitochondrial holocytochrome c-type synthase in X-linked dominant microphthalmia with linear skin defects syndrome". Am. J. Hum. Genet. 79 (5): 878–89. doi:10.1086/508474. PMC1698567. PMID 17033964.
^ a b"OMIM Entry - # 309801 - LINEAR SKIN DEFECTS WITH MULTIPLE CONGENITAL ANOMALIES 1; LSDMCA1".
^Wimplinger I, Shaw GM, Kutsche K (2007). "HCCS loss-of-function missense mutation in a female with bilateral microphthalmia and sclerocornea: a novel gene for severe ocular malformations?". Mol. Vis. 13: 1475–82. PMID 17893649.
Further reading
Wapenaar MC, Bassi MT, Schaefer L, et al. (1993). "The genes for X-linked ocular albinism (OA1) and microphthalmia with linear skin defects (MLS): cloning and characterization of the critical regions". Hum. Mol. Genet. 2 (7): 947–52. doi:10.1093/hmg/2.7.947. PMID 8364577.
Schaefer L, Ballabio A, Zoghbi HY (1997). "Cloning and characterization of a putative human holocytochrome c-type synthetase gene (HCCS) isolated from the critical region for microphthalmia with linear skin defects (MLS)". Genomics. 34 (2): 166–72. doi:10.1006/geno.1996.0261. PMID 8661044.
Van den Veyver IB, Subramanian S, Zoghbi HY (1998). "Genomic structure of a human holocytochrome c-type synthetase gene in Xp22.3 and mutation analysis in patients with Rett syndrome". Am. J. Med. Genet. 78 (2): 179–81. doi:10.1002/(SICI)1096-8628(19980630)78:2<179::AID-AJMG17>3.0.CO;2-K. PMID 9674913.
Schwarz QP, Cox TC (2002). "Complementation of a yeast CYC3 deficiency identifies an X-linked mammalian activator of apocytochrome c". Genomics. 79 (1): 51–7. doi:10.1006/geno.2001.6677. PMID 11827457.
Prakash SK, Cormier TA, McCall AE, et al. (2003). "Loss of holocytochrome c-type synthetase causes the male lethality of X-linked dominant microphthalmia with linear skin defects (MLS) syndrome". Hum. Mol. Genet. 11 (25): 3237–48. doi:10.1093/hmg/11.25.3237. PMID 12444108.
Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. Bibcode:2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC139241. PMID 12477932.
Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC528928. PMID 15489334.
Nakashima-Kamimura N, Asoh S, Ishibashi Y, et al. (2006). "MIDAS/GPP34, a nuclear gene product, regulates total mitochondrial mass in response to mitochondrial dysfunction". J. Cell Sci. 118 (Pt 22): 5357–67. doi:10.1242/jcs.02645. PMID 16263763.
Wimplinger I, Morleo M, Rosenberger G, et al. (2006). "Mutations of the mitochondrial holocytochrome c-type synthase in X-linked dominant microphthalmia with linear skin defects syndrome". Am. J. Hum. Genet. 79 (5): 878–89. doi:10.1086/508474. PMC1698567. PMID 17033964.
Wimplinger I, Shaw GM, Kutsche K (2007). "HCCS loss-of-function missense mutation in a female with bilateral microphthalmia and sclerocornea: a novel gene for severe ocular malformations?". Mol. Vis. 13: 1475–82. PMID 17893649.
External links
GeneReview/NIH/UW entry on Microphthalmia with Linear Skin Defects Syndrome
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