MIPEP
Identifiers
AliasesMIPEP, HMIP, MIP, mitochondrial intermediate peptidase, COXPD31
External IDsOMIM: 602241 MGI: 1917728 HomoloGene: 4337 GeneCards: MIPEP
Orthologs
SpeciesHumanMouse
Entrez

4285

70478

Ensembl

ENSG00000027001

ENSMUSG00000021993

UniProt

Q99797

A6H611

RefSeq (mRNA)

NM_005932

NM_027436

RefSeq (protein)

NP_005923

NP_081712

Location (UCSC)Chr 13: 23.73 – 23.89 MbChr 14: 61.02 – 61.14 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Mitochondrial intermediate peptidase is an enzyme that in humans is encoded by the MIPEP gene.[5] This protein is a critical component of human mitochondrial protein import machinery involved in the maturing process of nuclear coded mitochondrial proteins that with a mitochondrial translocation peptide, especially those OXPHOS-related proteins.[6]

Structure

Gene

The gene MIPEP encodes one metalloprotease that hydrolyzes peptide fragment of eight amino acids in lengths to process mitochondria-targeted proteins.[5] The human gene MIPEP has 21 Exons and locates at chromosome band13q12. Evidences showed that the human gene MIPEP is highly expressed in the heart, skeletal muscle, and pancreas, three organ systems that are frequently reported with OXPHOS disorders.

Protein

The human protein Mitochondrial intermediate peptidase is 80.6 kDa in size and composed of 713 amino acids. It contains a mitonchondria targeting peptide (Amino acid 1-35 of the peptide sequence). The mature protein has a theoretical pI of 6.03.[7]

Function

Working in concert with general mitochondrial processing peptidase (MPP), MIPEP plays critical role in the maturation of a specific class of nuclear-encoded precursor proteins characterized by the motif, XRX(f)(F/L/I)XX(T/S/G)XXXX(f).[8] Initially, peptidase MPP cleaves the precursors at positions two peptide bonds from the R residue, leaving a typical octapeptide at the protein N- terminus; subsequently, MIP cleaves the octapeptide, completing the final maturation of processed protein.[9][10] A recent study showed that mitochondrial intermediate peptidase can degrade the transmembrane receptor Notch at its S5 site and assist Notch protein maturation.[11]

Clinical significance

In a GWAS (Genome-Wide Association Study) study of Chinese population, a significant association between high myopia and a variant at chromosome band region 13q12.12 was reported. MIPEP and C1QTNF9B genes locate in the same locus and appear expressed in the retina and retinal pigment epithelium (RPE) and are thus likely to be associated with high myopia.[12] However, functional evidence linking MIPEP with myopia has yet to be provided.

Biallelic pathogenic variants in MIPEP present in infancy or early childhood with hypotonia (low muscle tone) and a rare type of cardiomyopathy, called left ventricular non-compaction. Cataracts may also be seen. In the four patients reported to date, the cardiomyopathy is progressive and results in death in the first few years of life.[13]

First identification

Description of the human clinical phenotype of an autosomal recessive neuromuscular disorder caused by deficiency of the mitochondrial intermediate presequence protease (MIP), encoded by the gene MIPEP, was first reported by a collective with a lead author Mohammad Eldomery and senior corresponding author V. Reid Sutton in 2016 in the journal Genome Medicine. The index subject was diagnosed with left ventricular non-compaction cardiomyopathy (LVNC) and Wolf-Parkinson-White syndrome at 5+1⁄2 months of age. In an attempt to identify the etiology of this cardiac phenotype, a series of tests were performed, including clinical whole exome sequencing. Because the clinical diagnostic laboratory did not identify pathogenic variants in known disease-associated genes, re-analysis of the exome data was performed by Dr. Mohammad Eldomery as part of the Baylor-Johns Hopkins Center for Mendelian Genomics. Biallelic variants were identified in the MIPEP gene, which was known in yeast and other organisms to be important in mitochondrial protein processing. Because LVNC is seen in other mitochondrial disorders, this was considered the best candidate gene. After interrogating the Baylor Genetic Laboratory clinical database and submitting the MIPEP gene to GeneMatcher, four other affected individuals from three families were identified with biallelic variants in MIPEP. In all four patients, the phenotype is LVNC with severe hypotonia and developmental delay. All of the affected individuals, with the exception of the index case, died before 2 years of age from cardiac failure. Seizures and cataracts were also noted in some of the affected individuals. The MIPEP variants included missense variants, stop variants as well as a 1.4 Megabase deletion involving the MIPEP gene.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000027001 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000021993 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 "Entrez Gene: MIPEP mitochondrial intermediate peptidase".
  6. ↑ Chew A, Buck EA, Peretz S, Sirugo G, Rinaldo P, Isaya G (Mar 1997). "Cloning, expression, and chromosomal assignment of the human mitochondrial intermediate peptidase gene (MIPEP)". Genomics. 40 (3): 493–6. doi:10.1006/geno.1996.4586. PMID 9073519.
  7. ↑ "Uniprot: Q99797 - MIPEP_HUMAN".
  8. ↑ Hendrick JP, Hodges PE, Rosenberg LE (Jun 1989). "Survey of amino-terminal proteolytic cleavage sites in mitochondrial precursor proteins: leader peptides cleaved by two matrix proteases share a three-amino acid motif". Proceedings of the National Academy of Sciences of the United States of America. 86 (11): 4056–60. Bibcode:1989PNAS...86.4056H. doi:10.1073/pnas.86.11.4056. PMC 287387. PMID 2657736.
  9. ↑ Isaya G, Kalousek F (1995). Mitochondrial intermediate peptidase. Methods in Enzymology. Vol. 248. pp. 556–67. doi:10.1016/0076-6879(95)48035-8. PMID 7674944.
  10. ↑ Isaya G, Sakati WR, Rollins RA, Shen GP, Hanson LC, Ullrich RC, Novotny CP (Aug 1995). "Mammalian mitochondrial intermediate peptidase: structure/function analysis of a new homologue from Schizophyllum commune and relationship to thimet oligopeptidases". Genomics. 28 (3): 450–61. doi:10.1006/geno.1995.1174. PMID 7490080.
  11. ↑ Lee SF, Srinivasan B, Sephton CF, Dries DR, Wang B, Yu C, Wang Y, Dewey CM, Shah S, Jiang J, Yu G (Aug 2011). "Gamma-secretase-regulated proteolysis of the Notch receptor by mitochondrial intermediate peptidase". The Journal of Biological Chemistry. 286 (31): 27447–53. doi:10.1074/jbc.M111.243154. PMC 3149338. PMID 21685396.
  12. ↑ Shi Y, Qu J, Zhang D, Zhao P, Zhang Q, Tam PO, et al. (Jun 2011). "Genetic variants at 13q12.12 are associated with high myopia in the Han Chinese population". American Journal of Human Genetics. 88 (6): 805–13. doi:10.1016/j.ajhg.2011.04.022. PMC 3113245. PMID 21640322.
  13. ↑ Eldomery MK, Akdemir ZC, Vögtle FN, Charng WL, Mulica P, Rosenfeld JA, et al. (2016). "MIPEP recessive variants cause a syndrome of left ventricular non-compaction, hypotonia, and infantile death". Genome Medicine. 8 (1): 106. doi:10.1186/s13073-016-0360-6. PMC 5088683. PMID 27799064.
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