HGNC Approved Gene Symbol: HCCS
SNOMEDCT: 721879006;
Cytogenetic location: Xp22.2 Genomic coordinates (GRCh38) : X:11,111,332-11,123,086 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp22.2 | Linear skin defects with multiple congenital anomalies 1 | 309801 | X-linked dominant | 3 |
HCCS is a highly conserved gene from fungi to metazoans that encodes holocytochrome c-type synthase, which is located on the outer surface of the inner mitochondrial membrane. HCCS catalyzes covalent attachment of heme to both cytochrome c (CYTC, or CYCS; 123970) and cytochrome c1 (CYTC1, or CYC1; 123980), which are crucial components of the mitochondrial respiratory chain (summary by Indrieri et al., 2013).
Using a cross-species conservation strategy, Schaefer et al. (1996) isolated an expressed sequence from a 450- to 550-kb critical region for a microphthalmia syndrome with linear skin defects (LSDMCA1, MLS; 309801) on Xp22 by screening a human embryo cDNA library. Northern analysis demonstrated a transcript of approximately 2.6 kb in all tissues examined, with weaker expression of 1.2- and 5.2-kb transcripts. The strongest expression was observed in heart and skeletal muscle. Sequence analysis of a 3-kb cDNA contig revealed an 807-bp open reading frame encoding a putative 268-amino acid protein. Comparison of the sequence with sequences in databases revealed homology with holocytochrome c-type synthetases. The human gene, symbolized HCCS, and the corresponding murine gene characterized by Schaefer et al. (1996) share 83% nucleotide sequence identity and 85% amino acid identity. The authors stated that, because of the lack of a neuromuscular phenotype in MLS, it is uncertain how the deletion of a mitochondrial holocytochrome synthetase would contribute to the phenotype seen in MLS. The expression pattern of the gene and knowledge of the function of holocytochrome synthetases suggested, however, that it is a good candidate for X-linked encephalomyopathies typically associated with mitochondrial dysfunction.
The HCCS gene contains 7 exons and spans 11 kb (Van den Veyver et al., 1998).
Schaefer et al. (1996) mapped the HCCS gene to chromosome Xp22 by sequence analysis.
By expression of wildtype and mutant human HCCS in yeast, Indrieri et al. (2013) found that the heme lyase activity of HCCS was not required for HCCS-dependent transport of Cytc into mitochondria. They concluded that binding of HCCS to apo-Cytc, rather than heme attachment, is critical for Cytc import into mitochondria.
Wimplinger et al. (2006) investigated a family with microphthalmia with linear skin defects (LSDMCA1, MLS; 309801) displaying phenotypic variability in which the youngest daughter, who had a classic phenotype and normal karyotype, had previously been studied by Morleo et al. (2005) and no pathogenic mutations found in the MID1, HCCS, or ARHGAP6 genes. DNA analysis revealed the presence of a heterozygous 8.6-kb deletion encompassing part of the HCCS gene (300056.0001) in the mother and 2 affected daughters; the deletion was not found in 3 sons or an unaffected daughter. Wimplinger et al. (2006) performed sequence analysis of the HCCS gene in 2 unrelated girls with MLS and normal karyotypes and identified heterozygosity for a de novo nonsense mutation (R197X, 300056.0002) and a de novo missense mutation (R217C, 300056.0003), respectively. All of the affected females had a skewed X-chromosome inactivation pattern in peripheral blood cells. Functional studies demonstrated that both the R197X and the R217C mutant proteins were unable to complement a Saccharomyces cerevisiae mutant deficient for the HCCS ortholog, in contrast to wildtype HCCS. Noting that cytochrome c is the final product of HCCS activity, Wimplinger et al. (2006) suggested that disturbance of both oxidative phosphorylation and the balance between apoptosis and necrosis, as well as X-inactivation patterns, may contribute to the variable phenotype observed in patients with MLS.
Exclusion Studies
Based on its chromosomal location and its role in the mitochondrial respiratory chain, HCCS was considered a candidate gene for Rett syndrome (RTT; 312750). No mutational abnormality of the gene was found in 20 RTT patients (Van den Veyver et al., 1998).
Prakash et al. (2002) noted that the human HCCS gene is located entirely inside the critical region defined for MLS. They generated a deletion mutant in the mouse that inactivated Hccs. Ubiquitous deletions generated in vivo led to lethality of hemizygous, homozygous, and heterozygous embryos early in development. This lethality was rescued by expression of the human HCCS gene from a transgenic BAC, resulting in viable homozygous, heterozygous, and hemizygous deleted mice with no apparent phenotype. In the presence of the HCCS transgene, the deletion was easily transmitted to subsequent generations. A single heterozygous deleted female that did not express human HCCS was identified, which is analogous to the low prevalence of the heterozygous MLS deletion in humans. The authors concluded that loss of HCCS causes the male lethality of MLS syndrome.
Indrieri et al. (2013) showed that morpholino-mediated knockdown of Hccs expression in medaka fish caused microphthalmia, microcephaly, and cardiovascular abnormalities, including failure of heart loop formation and pericardial edema, with death at hatching stage. Hccs-deficient embryos showed reduced complex III activity, whereas complexes I, II, and IV activities were normal. Western blot analysis revealed decreased content of Cytc in morphant embryos. Hccs morphants showed sustained apoptosis in retina compared with controls, leading to microphthalmia. Increased apoptosis was evident in several regions of the central nervous system, leading to microcephaly, but was not seen in other organs, including heart. Elevated apoptosis in Hccs morphants appeared to be due to activation and cytosolic release of caspase-9 (CASP9; 602234) in the absence of Cytc. Reactive oxygen species (ROS) content was elevated in Hccs morphants, and treatment of morphants with an ROS scavenger countered Casp9 activation and rescued microphthalmia and microcephaly. Indrieri et al. (2013) hypothesized that HCCS inhibits a noncanonical cell death pathway in brain and eye via enhanced mitochondrial ROS production and release of active CASP9.
In a mother and 2 daughters from a family with microphthalmia and linear skin defects (LSDMCA1; 309801), Wimplinger et al. (2006) identified an 8.6-kb deletion encompassing exons 1 and 2 and the first 83 bp of exon 3 of the HCCS gene. The youngest daughter, who had a classic phenotype and normal karyotype, had previously been studied by Morleo et al. (2005) and no pathogenic mutations found in the MID1, HCCS, or ARHGAP6 genes. The eldest daughter of the family had a milder phenotype; and the mother, who had no obvious signs of MLS, had a history of skin lesions in infancy that disappeared over time. The deletion was not found in 3 sons or an unaffected daughter.
In a 5-year-old girl with microphthalmia with linear skin defects syndrome (LSDMCA1; 309801), Wimplinger et al. (2006) identified heterozygosity for a de novo 589C-T transition in exon 6 of the HCCS gene, resulting in an arg197-to-ter (R197X) substitution. The mutation was not found in 50 female controls.
In a 9-year-old girl with microphthalmia and linear skin defects (LSDMCA1; 309801), Wimplinger et al. (2006) identified heterozygosity for a de novo 649C-T transition in exon 7 of the HCCS gene, resulting in an arg217-to-cys (R217C) substitution. The mutation was not found in 110 female controls.
Indrieri, A., Conte, I., Chesi, G., Romano, A., Quartararo, J., Tate, R., Ghezzi, D., Zeviani, M., Goffrini, P., Ferrero, I., Bovolenta, P., Franco, B. The impairment of HCCS leads to MLS syndrome by activating a non-canonical cell death pathway in the brain and eyes. EMBO Molec. Med. 5: 280-293, 2013. Note: Erratum: EMBO Molec. Med. 6: 849 only, 2014. [PubMed: 23239471] [Full Text: https://doi.org/10.1002/emmm.201201739]
Morleo, M., Pramparo, T., Perone, L., Gregato, G., Le Caignec, C., Mueller, R. F., Ogata, T., Raas-Rothschild, A., de Blois, M. C., Wilson, L. C., Zaidman, G., Zuffardi, O., Ballabio, A., Franco, B. Microphthalmia with linear skin defects (MLS) syndrome: clinical, cytogenetic, and molecular characterization of 11 cases. Am. J. Med. Genet. 137A: 190-198, 2005. [PubMed: 16059943] [Full Text: https://doi.org/10.1002/ajmg.a.30864]
Prakash, S. K., Cormier, T. A., McCall, A. E., Garcia, J. J., Sierra, R., Haupt, B., Zoghbi, H. Y., Van den Veyver, I. B. Loss of holocytochrome c-type synthetase causes the male lethality of X-linked dominant microphthalmia with linear skin defects (MLS) syndrome. Hum. Molec. Genet. 11: 3237-3248, 2002. [PubMed: 12444108] [Full Text: https://doi.org/10.1093/hmg/11.25.3237]
Schaefer, L., Ballabio, A., Zoghbi, H. Y. 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: 166-172, 1996. [PubMed: 8661044] [Full Text: https://doi.org/10.1006/geno.1996.0261]
Van den Veyver, I. B., Subramanian, S., Zoghbi, H. Y. 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: 179-181, 1998. [PubMed: 9674913] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19980630)78:2<179::aid-ajmg17>3.3.co;2-3]
Wimplinger, I., Morleo, M., Rosenberger, G., Iaconis, D., Orth, U., Meinecke, P., Lerer, I., Ballabio, A., Gal, A., Franco, B., Kutsche, K. Mutations of the mitochondrial holocytochrome c-type synthase in X-linked dominant microphthalmia with linear skin defects syndrome. Am. J. Hum. Genet. 79: 878-889, 2006. [PubMed: 17033964] [Full Text: https://doi.org/10.1086/508474]