Alternative titles; symbols
HGNC Approved Gene Symbol: PET100
Cytogenetic location: 19p13.2 Genomic coordinates (GRCh38): 19:7,629,793-7,631,956 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.2 | Mitochondrial complex IV deficiency, nuclear type 12 | 619055 | Autosomal recessive | 3 |
The PET100 gene encodes a protein involved in the biogenesis of mitochondrial complex IV (summary by Lim et al., 2014).
Using database analysis and protein profiling to identify human orthologs of yeast cytochrome c oxidase (COX) assembly proteins, followed by PCR of a heart cDNA library, Szklarczyk et al. (2012) cloned PET100. Mouse heart Pet100 localized to mitochondria.
Szklarczyk et al. (2012) showed that epitope-tagged PET100 copurified with the COX assembly protein COX17 (604813) and the COX IV subunit COX7A2 (123996) from transfected HEK293 cells.
Using immunofluorescence, Lim et al. (2014) showed that PET100 localized to the inner mitochondrial membrane in human fibroblasts. The PET100 protein assembles into a 300-kD complex that accumulates over time and is dependent on the mitochondrial membrane potential. The complex is distinct from endogenous complex IV.
Hartz (2012) mapped the PET100 gene to chromosome 19p13.2 based on an alignment of the PET100 sequence (GenBank AK124717) with the genomic sequence (GRCh37).
In 8 patients from 6 families with mitochondrial complex IV deficiency nuclear type 12 (MC4DN12; 619055), Lim et al. (2014) identified a homozygous mutation in the PET100 gene (M1?; 614770.0001), predicted to abolish the translation initiation codon. The mutation, which was found by homozygosity mapping combined with targeted sequencing of the candidate region, segregated with the disorder in all the families. Two of 81 additional Lebanese individuals who were referred for analysis of an OXPHOS defect were also found to carry the homozygous M1? mutation. All of the patients were of Lebanese descent living in Australia, and 6 of the families were known to be consanguineous. The findings were consistent with a founder effect in this population, and the mutation was estimated to be at least 520 years old. In vitro functional studies showed that mutant PET100 was not imported into the mitochondria and was incapable of assembly into the 300-kD complex. The findings suggested that the N terminus is essential for mitochondrial localization. Patient fibroblasts showed a significant loss of the complex IV holoenzyme, although the subunits were translated, suggesting an assembly defect. Overexpression of the wildtype gene in patient cells restored COX2 levels and complex IV assembly. The findings indicated that PET100 acts in the intermediate stage of complex IV assembly.
In 8 patients from 6 families with mitochondrial complex IV deficiency nuclear type 12 (MC4DN12; 619055) with a phenotype consistent with Leigh syndrome (see 256000), Lim et al. (2014) identified a homozygous c.3G-C transversion in exon 1 of the PET100 gene, predicted to abolish the translation initiation codon (met1-to-?; M1?). The mutation, which was found by homozygosity mapping combined with targeted sequencing of the candidate region, segregated with the disorder in all the families. It was not found in the dbSNP (build 132) or 1000 Genomes Project databases. Two of 81 additional Lebanese individuals who were referred for analysis of an OXPHOS defect were also found to carry the homozygous M1? mutation. All of the patients were of Lebanese descent living in Australia, and 6 of the families were consanguineous. The findings were consistent with a founder effect in this population, and the mutation was estimated to be at least 520 years old. The mutation could potentially lead to translation initiation at the next methionine at residue 10 (met10), which would yield a mutant protein, 1_9del. In vitro functional studies showed that mutant 1_9del was not imported into the mitochondria and was incapable of assembly into the 300-kD complex. The findings suggested that the N terminus is essential for mitochondrial localization. Patient fibroblasts showed a significant loss of the complex IV holoenzyme, although the subunits were translated, suggesting an assembly defect. Overexpression of the wildtype gene in patient cells restored COX2 levels and complex IV assembly.
In a newborn girl, born of consanguineous British Pakistani parents, with mitochondrial complex IV deficiency nuclear type 12 (MC4DN12; 619055), Olahova et al. (2015) identified a homozygous c.142C-T transition (c.142C-T, NM_001171155.1) in the PET100 gene, resulting in a gln48-to-ter (Q48X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient fibroblasts and skeletal muscle showed isolated impaired complex IV activity and a profound defect in COX assembly with decreased steady-state levels of complex IV proteins and decreased amounts of fully assembled complex IV.
Hartz, P. A. Personal Communication. Baltimore, Md. 8/17/2012.
Lim, S. C., Smith, K. R., Stroud, D. A., Compton, A. G., Tucker, E. J., Dasvarma, A., Gandolfo, L. C., Marum, J. E., McKenzie, M., Peters, H. L., Mowat, D., Procopis, P. G., Wilcken, B., Christodoulou, J., Brown, G. K., Ryan, M. T., Bahlo, M., Thorburn, D. R. A founder mutation in PET100 causes isolated complex IV deficiency in Lebanese individuals with Leigh syndrome. Am. J. Hum. Genet. 94: 209-222, 2014. [PubMed: 24462369] [Full Text: https://doi.org/10.1016/j.ajhg.2013.12.015]
Olahova, M., Haack, T. B., Alston, C. L., Houghton, J. A. C., He, L., Morris, A. A. M., Brown, G. K., McFarland, R., Chrzanowska-Lightowlers, Z. M. A., Lightowlers, R. N., Prokisch, H., Taylor, R. W. A truncating PET100 variant causing fatal infantile lactic acidosis and isolated cytochrome c oxidase deficiency. Europ. J. Hum. Genet. 23: 935-939, 2015. [PubMed: 25293719] [Full Text: https://doi.org/10.1038/ejhg.2014.214]
Szklarczyk, R., Wanschers, B. F. J., Cuypers, T. D., Esseling, J. J., Riemersma, M., van den Brand, M. A. M., Gloerich, J., Lasonder, E., van den Heuvel, L. P., Nijtmans, L. G., Huynen, M. A. Iterative orthology prediction uncovers new mitochondrial proteins and identifies C12orf62 as the human ortholog of COX14, a protein involved in the assembly of cytochrome c oxidase. Genome Biol. 13: R12, 2012. Note: Electronic Article. [PubMed: 22356826] [Full Text: https://doi.org/10.1186/gb-2012-13-2-r12]