Mitochondrial Intermediate Peptidase (MIPEP) is a nuclear gene encoding a metalloprotease which is required for processing precursor mitochondrial proteins. Cytosolic proteins bound for mitochondria exhibit an N-terminal sequence that is essential for translocation and import into the organelle; this sequence is removed by a peptidase in the mitochondrion. A group of these proteins undergo a second processing step in which MIPEP excises an additional 8 amino acid peptide fragment before a mature stable protein is formed. MIPEP activity is stimulated by divalent cations and is involved in maturing proteins involved in oxidative phosphorylation; its function is essential to mitochondrial biogenesis and ATP production.
MIPEP dysfunction causes Combined Oxidative Phosphorylation Deficiency 31. Functional studies on a homologous yeast protein additionally indicate a role of the protease in mitochondrial iron homeostasis, therefore it is thought to be implicated in Friedrich’s Ataxia. A significant association between MIPEP variants and myopia has also been established.
MIPEP is located on the q arm of chromosome 13 and is 159,261 base pairs long ranging from 23,730,188 to 23,889,448 base pairs pter. The gene contains 19 exons and translates into a 713aa long protein with a molecular weight of 80,641Da. MIPEP belongs to the peptidase M3 family and is essential for maturation of mitochondrial enzymes that facilitate ATP production. MIPEP is ubiquitously expressed, with highest expression found in the esophagus, adrenal gland, tonsils, uterus, and salivary glands. It is highly abundant in tissues that exhibit heavy energy consumption such as the heart and skeletal muscle. 5 possible alternatively spliced variations of MIPEP have been identified.
Homozygous or compound heterozygous loss-of-function mutations in MIPEP, including missense, nonsense, and deletion mutations, result in autosomal recessive Combined Oxidative Phosphorylation Deficiency 31. Identical missense mutations in the yeast homologue protein were found to be deleterious causing either reduced protease activity or lack of protein localization to mitochondria. Furthermore, functional studies in yeast indicate a link between MIPEP dysfunction and Friedrich’s Ataxia, and a genome wide association study indicates a significant link between MIPEP variants and myopia.
Al-Shamsi et al., 2016 performed Whole Exome Sequencing (WES) in 85 Emirati patients who were admitted to the metabolic unit with un-diagnosable inborn errors of metabolism and other genetic disorders. Among the cohort in whom variants of uncertain significance were likely pathogenic, 1 patient was diagnosed with Combined Oxidative Posphorylation Deficiency 31. A homozygous missense transition in MIPEP (c.1027A>G; p.Lys343Glu) was identified as the probable cause. Functional studies by Eldomery et al. 2016 of the same mutation in yeast yielded severely reduced protease activity and a buildup of unprocessed substrates.
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