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MITOCHONDRIAL CONTACT SITE AND CRISTAE ORGANIZING SYSTEM, 13-KD SUBUNIT; MICOS13

MITOCHONDRIAL CONTACT SITE AND CRISTAE ORGANIZING SYSTEM, 13-KD SUBUNIT; MICOS13

Alternative titles; symbolsMIC13MICOS COMPLEX, 13-KD SUBUNITQIL1CHROMOSOME 19 OPEN READING FRAME 70; C19ORF70HGNC Approved Gene Symbol: MICOS13Cytogenetic locati...

Alternative titles; symbols

  • MIC13
  • MICOS COMPLEX, 13-KD SUBUNIT
  • QIL1
  • CHROMOSOME 19 OPEN READING FRAME 70; C19ORF70

HGNC Approved Gene Symbol: MICOS13

Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38): 19:5,678,421-5,680,515 (from NCBI)

▼ Description
The mitochondrial contact site and cristae junction organizing system (MICOS) is an approximately 700-kD complex that dynamically regulates mitochondrial membrane architecture. The MICOS13 gene encodes a MICOS subunit that localizes to the inner mitochondrial membrane at cristae junctions and is required for cristae junction integrity, cristae morphology, and mitochondrial function (Guarani et al., 2015).

▼ Cloning and Expression
By immunoprecipitation and mass spectrometric analysis of proteins that associated with isolated MICOS in human 293T and HCT116 cells, Guarani et al. (2015) identified C19ORF70, which they called QIL1. The deduced 118-amino acid protein has a conserved transmembrane helix. Database analysis identified orthologs of QIL1 across metazoans, including Drosophila. Differential extraction of isolated mitochondria suggested that QIL1 is a protein of the inner mitochondrial membrane. Transmission immunoelectron microscopy localized QIL1 to cristae junctions.

▼ Gene Function
By immunopurification of MICOS subunits subject to differential detergent extraction, Guarani et al. (2015) found that the strongest MICOS binding partners for QIL1 were MIC10 (MINOS1; 616574) and MIC60 (IMMT; 600378). RNA interference-mediated depletion of QIL1 in HeLa cells disrupted mitochondrial cristae morphology, with loss of cristae junctions and the presence of inner membrane structures composed of concentric rings. Moreover, depletion of QIL1 resulted in substantial reduction in mitochondrial respiration. Knockdown of Qil1 in Drosophila larva resulted in similar loss of cristae junctions and formation of concentric stacks of inner membrane inside the matrix compartment. Knockdown of QIL1 reduced the total protein abundance of MICOS subunits MIC26 (APOO; 300753) and MIC27 (APOOL; 300955) and resulted in accumulation of MIC19 (CHCHD3; 613748), MIC25 (CHCHD6; 615634), and MIC60 in an approximately 500-kD MICOS subcomplex, with concomitant reduction of mature 700-kD MICOS. Guarani et al. (2015) concluded that QIL1 is required for MICOS assembly, cristae junction integrity, and cristae morphology.

▼ Mapping
Hartz (2015) mapped the C19ORF70 gene to chromosome 19p13.3 based on an alignment of the C19ORF70 sequence (GenBank BC009557) with the genomic sequence (GRCh38).

▼ Molecular Genetics
In 2 sibs, born of consanguineous parents of Muslim origin, with combined oxidative phosphorylation deficiency-37 (COXPD37; 618329), Zeharia et al. (2016) identified a homozygous frameshift mutation in the MICOS13 gene (616658.0001). The mutation, which was found by a combination of homozygosity mapping and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient fibroblasts showed absence of the MICOS13 protein as well as reduced levels of other MICOS subunits, indicating a defect in assembly of the complex. Electron microscopic analysis of patient fibroblasts and skeletal muscle tissue showed abnormal mitochondrial cristae morphology, including loss of cristae structure and the appearance of abnormal 'swirl' structures. Patient mitochondria were enlarged and swollen or rounded and elongated, indicating a loss of architecture. These abnormalities could be rescued by expression of wildtype MICOS13.

In 2 sibs with COXPD37, Guarani et al. (2016) identified a homozygous splice site mutation in the MICOS13 gene (616658.0002). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient fibroblasts showed absence of the MICOS13 protein as well as reduced levels of other MICOS subunits, indicating a defect in assembly of the complex. Patient fibroblasts also showed a growth defect upon glucose withdrawal, consistent with a defect in mitochondrial function.

In a girl, born of consanguineous Iraqi parents, with COXPD37, Godiker et al. (2018) identified a homozygous splice site mutation in the MICOS13 gene (616658.0003). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. There was no full-length MICOS13 detected in patient cells, consistent with a loss of function.

▼ ALLELIC VARIANTS ( 3 Selected Examples):

.0001 COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 37
MICOS13, 1-BP DEL, 44C
In 2 sibs, born of consanguineous parents of Muslim origin, with combined oxidative phosphorylation deficiency-37 (COXPD37; 618329), Zeharia et al. (2016) identified a homozygous 1-bp deletion (c.44delC, NM_205767) in the MICOS13 gene, resulting in a frameshift and premature termination (Gly15GlufsTer75). The mutation, which was found by a combination of homozygosity mapping and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the ExAC database (August 2015) or in 650 ethnically matched controls. Western blot analysis of patient cells showed undetectable levels of MICOS13, consistent with a loss of function.

.0002 COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 37
MICOS13, IVS1AS, G-A, -1
In 2 sibs with combined oxidative phosphorylation deficiency-37 (COXPD37; 618329), Guarani et al. (2016) identified a homozygous G-to-A transition in intron 1 of the MICOS13 gene (c.30-1G-A, NM_205767.2), which was shown to result in a splicing abnormality, a frameshift, and premature termination. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient fibroblasts showed absence of the MICOS13 protein as well as reduced levels of other MICOS subunits, indicating a defect in assembly of the complex.

.0003 COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 37
MICOS13, IVS3AS, A-G, -2
In a girl, born of consanguineous Iraqi parents, with combined oxidative phosphorylation deficiency-37 (COXPD37; 618329), Godiker et al. (2018) identified a homozygous A-to-G transition in intron 3 of the MICOS13 gene (c.260-2A-G), which was shown to result in abnormal splicing. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. There was no full-length MICOS13 detected in patient cells, consistent with a loss of function.

Tags: 19p13.3