HGNC Approved Gene Symbol: MIPEP
Cytogenetic location: 13q12.12 Genomic coordinates (GRCh38): 13:23,730,189-23,889,400 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 13q12.12 | Combined oxidative phosphorylation deficiency 31 | 617228 | Autosomal recessive | 3 |
The MIPEP gene encodes mitochondrial intermediate peptidase (MIP; EC 3.4.24.59), which performs the final step in processing a specific class of nuclear-encoded proteins targeted to the mitochondrial matrix or inner membrane (Kalousek et al., 1992).
Isaya et al. (1992) cloned and sequenced rat liver MIP. Using a rat MIP cDNA as a probe, Chew et al. (1997) isolated a cDNA, termed MIPEP, from a human liver cDNA library. The MIPEP open reading frame encodes a 713-amino acid protein that is 92% homologous to rat MIP and 54% homologous to yeast MIP. Northern blot analysis showed that the 2.4-kb mRNA is differentially expressed in human tissues, with highest levels in heart, skeletal muscle, and pancreas, 3 organ systems that are frequently affected in OXPHOS disorders.
Chew et al. (1997) found that, like yeast MIP, human MIP is primarily involved in the maturation of oxidative phosphorylation (OXPHOS)-related proteins.
Friedreich ataxia (FRDA; 229300) is a neurodegenerative disease typically caused by deficiency of frataxin (FXN; 606829), a mitochondrial protein. In Saccharomyces cerevisiae, lack of the yeast homolog of frataxin (YFH1) results in mitochondrial iron accumulation, suggesting that frataxin is required for mitochondrial iron homeostasis and that FRDA results from oxidative damage secondary to mitochondrial iron overload. Branda et al. (1999) showed that YFH1 interacts functionally with yeast mitochondrial intermediate peptidase (YMIP), a metalloprotease required for maturation of ferrochelatase (612386) and other iron-utilizing proteins. YMIP is activated by ferrous iron in vitro, and loss of YMIP activity leads to mitochondrial iron depletion, suggesting that YMIP is part of a feedback loop in which iron stimulates maturation of YMIP substrates and this in turn promotes mitochondrial iron uptake. Consistent with this suggestion, YMIP is active and promotes mitochondrial iron accumulation in a mutant lacking the yeast frataxin homolog, while genetic inactivation of YMIP in this mutant leads to a 2-fold reduction in mitochondrial iron levels. Branda et al. (1999) proposed that YFH1 maintains mitochondrial iron homeostasis both directly, by promoting iron export, and indirectly, by regulating iron levels and therefore YMIP activity, which promotes mitochondrial iron uptake. The authors suggested that human MIP may contribute to the functional effects of frataxin deficiency and the clinical manifestations of FRDA.
Chew et al. (2000) demonstrated that MIPEP can complement a yeast knockout mutant lacking YMIP, demonstrating that the genes are functional homologs. Primer extension analysis identified a major transcript of the MIPEP gene expressed differentially and predominantly in tissues with high oxygen consumption. Northern blot analysis of brain tissue detected uniform expression of MIPEP in all regions tested, whereas FXN was overexpressed in cerebellum and spinal cord, with weaker expression in occipital and frontal lobes.
By genomic sequence analysis, Chew et al. (2000) determined that the MIPEP gene spans 57 kb and contains 19 exons.
Chew et al. (1997) mapped the MIPEP gene to chromosome 13q12 by fluorescence in situ hybridization. By multipoint linkage analysis, Chew et al. (2000) mapped the MIPEP gene within a 7-cM interval between markers D13S283 and D13S217 on 13q12.
In 4 unrelated children with combined oxidative phosphorylation deficiency-31 (COXPD31; 617228), Eldomery et al. (2016) identified homozygous or compound heterozygous mutations in the MIPEP gene (602241.0001-602241.0006). The mutations were found by whole-exome sequencing and segregated with the disorder in the families for whom parental DNA was available. There were 5 missense mutations, 1 nonsense mutation, and 1 large deletion encompassing the MIPEP gene. In vitro functional expression assays using the yeast homolog Oct1 demonstrated that the missense mutations had deleterious effects. The yeast mutations L339F (human L306F; 602241.0003) and K376E (human K343E; 602241.0005) resulted in a severe decrease of Oct1 protease activity with accumulation of nonprocessed Oct1 substrates, resulting in impaired viability under respiratory growth conditions. The L83Q (human L71Q; 602241.0002) mutant failed to localize to the mitochondria and fully abolished Oct1 processing. The findings were consistent with a loss of function. The patients had developmental delay, hypotonia, left ventricular noncompaction, and variable seizures; 3 patients died before 2 years of age.
In a 20-year-old man with COXPD31, Pulman et al. (2021) identified compound heterozygous mutations in the MIPEP gene (602241.0003 and 602241.0007) that segregated with the disorder in the family. Evaluation of patient fibroblasts demonstrated decreased MIP protein and decreased abundance of OXPHOS complexes I, IV, and V, suggesting that MIP is an important regulator of OXPHOS abundance. Pulman et al. (2021) showed accumulation of the long isoform of the large mitochondrial subunit protein bL12m (MRPL12; 602375) in patient fibroblasts, indicating inhibition of MIP-mediated processing. Pulman et al. (2021) further demonstrated impaired MIP-mediated processing of 7 proteins predicted to be MIP substrates, including OXPHOS complex I subunits NDUFV2 (600532) and NDUFS8 (602141), complex II subunit SDHA (600857), complex V subunits ATP5PO (600828) and ATP5F1 (ATP5PB; 603270), and the inner mitochondrial insertase OXA1L (601066).
In a 4.5-year-old boy (patient 1) with combined oxidative phosphorylation deficiency-31 (COXPD31; 617228), Eldomery et al. (2016) identified compound heterozygous missense mutations in the MIPEP gene: a c.1745T-G transversion (c.1745T-G, NM_005932), resulting in a leu582-to-arg (L582R) substitution, and a c.212T-A transversion, resulting in a leu71-to-gln (L71Q; 602241.0002) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither mutation was present in the 1000 Genomes Project, dbSNP, Exome Variant Server, or ExAC databases. Both mutations occurred at highly conserved residues. In vitro functional expression assays using the yeast homolog Oct1 demonstrated that the L83Q (human L71Q) mutant failed to localize to the mitochondria and fully abolished Oct1 processing. These findings were consistent with a loss-of-function effect of that mutation. Functional studies of the L582R mutation were not performed.
For discussion of the c.212T-A transversion (c.212T-A, NM_005932) in the MIPEP gene, resulting in a leu71-to-gln (L71Q) substitution, that was found in compound heterozygous state in a patient with combined oxidative phosphorylation deficiency-31 (COXPD31; 617228) by Eldomery et al. (2016), see 602241.0001.
In a girl (patient 2) of European descent with combined oxidative phosphorylation deficiency-31 (COXPD31; 617228), Eldomery et al. (2016) identified compound heterozygous mutations in the MIPEP gene: a c.916C-T transition (c.916C-T, NM_005932), resulting in a leu306-to-phe (L306F) substitution at a conserved residue, and a c.1804G-T transversion, resulting in a glu602-to-ter (E602X; 602241.0004) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The heterozygous L306F mutation was found at a low frequency in the ExAC database (8.2 x 10(-6)), whereas E602X was not found in the 1000 Genomes Project, dbSNP, Exome Variant Server, or ExAC databases. In vitro functional expression assays using the yeast homolog Oct1 demonstrated that the L339F (human L306F) mutation resulted in a severe decrease of Oct1 protease activity with accumulation of nonprocessed Oct1 substrates, resulting in impaired viability under respiratory growth conditions.
In a 20-year-old man with COXPD31, Pulman et al. (2021) identified compound heterozygous mutations in the MIPEP gene: L306F and a c.1970+2T-A transversion (602241.0007) in intron 17, predicted to result in a frameshift and premature termination (Ala658fsTer38). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Sequencing of cDNA from the patient demonstrated an aberrant transcript retaining 8 nucleotides after exon 17, possibly resulting in a truncated protein. Evaluation of patient fibroblasts demonstrated decreased MIP and abnormal accumulation of the long isoform of the large mitochondrial subunit protein bL12m, indicating inhibition of MIP-mediated processing. Pulman et al. (2021) also demonstrated impaired MIP-mediated processing of 7 proteins predicted to be MIP substrates.
For discussion of the c.1804G-T transversion (c.1804G-T, NM_005932) in the MIPEP gene, resulting in a glu602-to-ter (E602X) substitution, that was found in compound heterozygous state in a patient with combined oxidative phosphorylation deficiency-31 (COXPD31; 617228) by Eldomery et al. (2016), see 602241.0003.
In a boy (patient 3), born of consanguineous Egyptian parents, with combined oxidative phosphorylation deficiency-31 (COXPD31; 617228), Eldomery et al. (2016) identified a homozygous c.1027A-G transition (c.1027A-G, NM_005932) in the MIPEP gene, resulting in a lys343-to-glu (K343E) substitution at a highly conserved residue. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing; segregation studies in the family were not possible due to lack of parental DNA. The mutation was not present in the 1000 Genomes Project, dbSNP, Exome Variant Server, or ExAC databases. In vitro functional expression assays using the yeast homolog Oct1 demonstrated that the K376E (human K343E) mutation resulted in a severe decrease of Oct1 protease activity with accumulation of non-processed Oct1 substrates, resulting in impaired viability under respiratory growth conditions.
In a male infant (patient 4) with combined oxidative phosphorylation deficiency-31 (COXPD31; 617228), Eldomery et al. (2016) identified compound heterozygosity for defects of the MIPEP gene: a c.1534C-G transversion (c.1534C-G, NM_005932) resulting in a his512-to-asp (H512D) substitution at a highly conserved residue, and a 1.4-Mb deletion of 13q12.12 that included that MIPEP gene. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The heterozygous H512D mutation was found at a low frequency in the ExAC database (3.2 x 10(-5)). Functional studies of the H512D variant were not performed.
For discussion of the c.1970+2T-A transversion (c.1970+2T-A, NM_005932.3) in intron 17 of the MIPEP gene, predicted to result in a frameshift and premature termination (Ala658fsTer38), that was found in compound heterozygous state in a patient with combined oxidative phosphorylation deficiency-31 (COXPD31; 617228) by Pulman et al. (2021), see 602241.0003.
Branda, S. S., Yang, Z., Chew, A., Isaya, G. Mitochondrial intermediate peptidase and the yeast frataxin homolog together maintain mitochondrial iron homeostasis in Saccharomyces cerevisiae. Hum. Molec. Genet. 8: 1099-1110, 1999. [PubMed: 10332043] [Full Text: https://doi.org/10.1093/hmg/8.6.1099]
Chew, A., Buck, E. A., Peretz, S., Sirugo, G., Rinaldo, P., Isaya, G. Cloning, expression, and chromosomal assignment of the human mitochondrial intermediate peptidase gene (MIPEP). Genomics 40: 493-496, 1997. [PubMed: 9073519] [Full Text: https://doi.org/10.1006/geno.1996.4586]
Chew, A., Sirugo, G., Alsobrook, J. P., II, Isaya, G. Functional and genomic analysis of the human mitochondrial intermediate peptidase, a putative protein partner of frataxin. Genomics 65: 104-112, 2000. [PubMed: 10783257] [Full Text: https://doi.org/10.1006/geno.2000.6162]
Eldomery, M. K., Akdemir, Z. C., Vogtle, F.-N., Charng, W.-L., Mulica, P., Rosenfeld, J. A., Gambin, T., Gu, S., Burrage, L. C., Al Shamsi, A., Penney, S., Jhangiani, S. N., and 20 others. MIPEP recessive variants cause a syndrome of left ventricular non-compaction, hypotonia, and infantile death. Genome Med. 8: 106, 2016. Note: Electronic Article. [PubMed: 27799064] [Full Text: https://doi.org/10.1186/s13073-016-0360-6]
Isaya, G., Kalousek, F., Rosenberg, L. E. Sequence analysis of rat mitochondrial intermediate peptidase: similarity to zinc metallopeptidases and to a putative yeast homologue. Proc. Nat. Acad. Sci. 89: 8317-8321, 1992. [PubMed: 1518864] [Full Text: https://doi.org/10.1073/pnas.89.17.8317]
Kalousek, F., Isaya, G., Rosenberg, L. E. Rat liver mitochondrial intermediate peptidase (MIP): purification and initial characterization. EMBO J. 11: 2803-2809, 1992. [PubMed: 1322290] [Full Text: https://doi.org/10.1002/j.1460-2075.1992.tb05347.x]
Pulman, J., Ruzzenente, B., Horak, M., Barcia, G., Boddaert, N., Munnich, A., Rotig, A., Metodiev, M. D. Variants in the MIPEP gene presenting with complex neurological phenotype without cardiomyopathy, impair OXPHOS protein maturation and lead to a reduced OXPHOS abundance in patient cells. Molec. Genet. Metab. 134: 267-273, 2021. [PubMed: 34620555] [Full Text: https://doi.org/10.1016/j.ymgme.2021.09.005]