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MISATO 1, MITOCHONDRIAL DISTRIBUTION AND MORPHOLOGY REGULATOR; MSTO1

MISATO 1, MITOCHONDRIAL DISTRIBUTION AND MORPHOLOGY REGULATOR; MSTO1

Alternative titles; symbolsMISATO, DROSOPHILA, HOMOLOG OFHGNC Approved Gene Symbol: MSTO1Cytogenetic location: 1q22 Genomic coordinates (GRCh38): 1:155,610,1...

Alternative titles; symbols

  • MISATO, DROSOPHILA, HOMOLOG OF

HGNC Approved Gene Symbol: MSTO1

Cytogenetic location: 1q22 Genomic coordinates (GRCh38): 1:155,610,169-155,614,966 (from NCBI)

▼ Description

MSTO1 associates with the mitochondrial outer membrane and has a role in mitochondrial fusion and intracellular distribution (Kimura and Okano, 2007).

▼ Cloning and Expression

Miklos et al. (1997) cloned Drosophila misato, which encodes a deduced protein with peptide motifs found in alpha-tubulin (see 191110), beta-tubulin (TUBB; 191130), and gamma-tubulin (see 191135), as well as a motif related to myosin heavy chain proteins (see 160730). By EST database analysis, Miklos et al. (1997) identified a putative human ortholog of Drosophila misato.

Kimura and Okano (2007) cloned full-length human MSTO1, which encodes a deduced 570-amino acid protein with a calculated molecular mass of 61.8 kD. RT-PCR detected MSTO1 expression in all human tissues examined, with highest content in testis and muscle. Western blot analysis detected MSTO1 protein in all human cell lines examined. Immunohistochemical analysis of HeLa cells localized endogenous MSTO1 to mitochondria. Subfractionation of HeLa cell mitochondria and biochemical extraction revealed loose association of MSTO1 with the outer face of mitochondrial outer membranes.

Nasca et al. (2017) and Gal et al. (2017) independently determined that MSTO1 is a soluble protein predominantly localized to the cytoplasm with some localization to the mitochondria. Gal et al. (2017) suggested that it may interact with the outer mitochondrial membrane during fusion.

▼ Mapping

Kimura and Okano (2007) stated that the MSTO1 gene maps to chromosome 1q22.

▼ Gene Function

Using short interfering RNA, Kimura and Okano (2007) found that knockdown of MSTO1 in HeLa cells disturbed the mitochondrial network, resulting in growth defects and fragmented mitochondria. A subset of knockdown cells also showed fragmented nuclei, characteristic of apoptosis. Overexpression of fluorescence-tagged MSTO1 in COS-7 cells resulted in perinuclear mitochondrial clustering, abnormal microtubules, structurally abnormal nuclei, a subset of cells that completely lacked nuclei, and cell death. Kimura and Okano (2007) proposed that MSTO1 has a critical role in mitochondrial fusion and that other cellular abnormalities due to loss of MSTO1 are due to mitochondrial dysfunction.

Nasca et al. (2017) found that overexpression of MSTO1 resulted in fragmentation and perinuclear aggregation of mitochondria.

▼ Molecular Genetics

In 3 patients from 2 unrelated families with mitochondrial myopathy and ataxia (MMYAT; 617675), Nasca et al. (2017) identified compound heterozygous mutations in the MSTO1 gene (617619.0001-617619.0004). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Fibroblasts derived from 2 affected sisters showed clear fragmentation of the mitochondrial network compared to controls, and dynamic studies showed a decrease in the activity of mitochondrial network formation, mitochondrial fusion, and mitochondrial movements. Fibroblasts derived from the sisters also showed reduced mtDNA content (39% and 68%, respectively).

In a mother and her 3 adult children with MMYAT, Gal et al. (2017) identified a heterozygous missense mutation in the MSTO1 gene (V8M; 617619.0005). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient fibroblasts showed increased aggregated mitochondria and fragmented mitochondria, as well as dynamic abnormalities in mitochondrial network formation, fusion, and movements compared to controls. The decrease in fusion activity could be quantified as a 40% decrease compared to controls, and could be rescued by transfection of wildtype MSTO1. However, further studies showed no impairment of calcium signaling, basal respiration, or mitochondrial bioenergetics. Similar findings were observed in HeLa cells with siRNA-mediated MSTO1 knockdown.

Iwama et al. (2018) reported 2 unrelated girls with MMYAT and compound heterozygous mutations in the MSTO1 gene. Both had the same missense mutation (R279H; 617619.0006); one had a splice site mutation (617619.0007) and the other had a nonsense (Q27X; 617619.0008) mutation. The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. The parents in both families were shown to be carriers.

Li et al. (2020) reported 2 brothers with MMYAT who were compound heterozygous for mutations in the MSTO1 gene: the R279H mutation and a 1-bp deletion (617619.0009). The mutations, which were located in highly conserved regions, were identified by whole-exome sequencing and confirmed by Sanger sequencing. The parents were confirmed to be carriers.

▼ Animal Model

Miklos et al. (1997) found that knockout of misato in Drosophila caused irregular chromosomal segregation at cell division. Misato mutant larvae were almost devoid of imaginal disk tissue, had reduced brain size, and died before the late third-instar larval stage.

▼ ALLELIC VARIANTS ( 9 Selected Examples):

.0001 MYOPATHY, MITOCHONDRIAL, AND ATAXIA, AUTOSOMAL RECESSIVE
MSTO1, ARG345CYS (rs150075701)

In 2 sisters, born of unrelated parents, with autosomal recessive mitochondrial myopathy and ataxia (MMYAT; 617675), Nasca et al. (2017) identified compound heterozygous missense mutations in the MSTO1 gene: a c.1033C-T transition (c.1033C-T, NM_018116.3) in exon 10, resulting in an arg345-to-cys (R345C) substitution, and a c.1128C-A transversion in exon 11, resulting in a phe376-to-leu (F376L; 617619.0002) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The substitutions occurred at highly conserved residues and were not found in the dbSNP or 1000 Genomes Project databases. In the ExAC database, F376L was not found, but R345C was found at a very low frequency (1 in over 120,000 alleles). Analysis of patient cells showed very low levels of MSTO1 protein (about 15% residual levels) compared to controls, suggesting that the mutations affect the stability of the protein.

.0002 MYOPATHY, MITOCHONDRIAL, AND ATAXIA, AUTOSOMAL RECESSIVE
MSTO1, PHE376LEU

For discussion of the c.1128C-A transversion (c.1128C-A, NM_018116.3) in the MSTO1 gene, resulting in a phe376-to-leu (F376L) substitution, that was found in compound heterozygous state in 2 sisters with autosomal recessive mitochondrial myopathy and ataxia (MMYAT; 617675) by Nasca et al. (2017), see 617619.0001.

.0003 MYOPATHY, MITOCHONDRIAL, AND ATAXIA, AUTOSOMAL RECESSIVE
MSTO1, THR324ILE

In a boy with autosomal recessive mitochondrial myopathy and ataxia (MMYAT; 617675), Nasca et al. (2017) identified compound heterozygous mutations in the MSTO1 gene: a c.971C-T transition (c.971C-T, NM_018116.3) in exon 10, resulting in a thr324-to-ile (T324I) substitution, and a G-to-A transition (c.966+1G-A; 617619.0004) in intron 9, resulting in a splice site alteration. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Both mutations were found at a very low frequency in the ExAC database (less than 0.00004). Analysis of patient cells showed that the splice site mutation resulted in an aberrant transcript lacking exon 9.

.0004 MYOPATHY, MITOCHONDRIAL, AND ATAXIA, AUTOSOMAL RECESSIVE
MSTO1, IVS9DS, G-A, +1

For discussion of the G-to-A transition (c.966+1G-A, NM_018116.3) in intron 9 of the MSTO1 gene, resulting in a splice site alteration that was found in compound heterozygous state in a patient with autosomal recessive mitochondrial myopathy and ataxia (MMYAT; 617675) by Nasca et al. (2017), see 617619.0003.

.0005 MYOPATHY, MITOCHONDRIAL, AND ATAXIA, AUTOSOMAL DOMINANT
MSTO1, VAL8MET (rs762798018)

In a Hungarian woman and her 3 adult children with autosomal dominant mitochondrial myopathy and ataxia (MMYAT; 617675), Gal et al. (2017) identified a heterozygous c.22G-A transition (rs762798018) in the MSTO1 gene, resulting in a val8-to-met (V8M) substitution at a highly conserved residue. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found in the 1000 Genomes Project or Exome Sequencing Project databases, but was found at a low frequency (0.003%) in the ExAC database. Patient fibroblasts showed approximately 50% decreased MSTO1 mRNA and protein expression compared to controls.

.0006 MYOPATHY, MITOCHONDRIAL, AND ATAXIA, AUTOSOMAL RECESSIVE
MSTO1, ARG279HIS

In 2 unrelated patients, a 13-year-old girl (patient 1) and a 3-year-old girl (patient 2), with autosomal recessive mitochondrial myopathy and ataxia (MMYAT; 617675), Iwama et al. (2018) identified compound heterozygous mutations in the MSTO1 gene. Both patients had a c.836G-A transition, resulting in an arg279-to-his (R279H) substitution; patient 1 also had a c.1099G-A transition (c.1099-1G-A; 617619.0007) in intron 10, resulting in a frameshift and a premature termination codon (Val367TrpfsTer2) predicted to undergo nonsense-mediated mRNA decay, and patient 2 had a c.79C-T transition, resulting in a gln27-to-ter (Q27X; 617619.0008) substitution in the segment II tubulin-like domain. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. The parents were confirmed to be mutation carriers. The Q27X mutation was not present in the ExAC database and the c.1099-1G-A variant was present at low frequency; however, the R279H variant was present in homozygous state in 1 individual. Iwama et al. (2018) hypothesized that the R279H mutation allows for some residual function and is only pathogenic when combined with a protein-truncating mutation.

In 2 sibs with MMYAT, Li et al. (2020) identified compound heterozygous mutations in the MSTO1 gene: the c.836G-A transition (c.836G-A, NM_018116.3) in exon 9, resulting in the R279H substitution, and a 1-bp deletion (c.1259delG; 617619.0009) in exon 11, predicted to result in a frameshift and premature termination (Gly420ValfsTer2). The mutations, which were identified by whole-exome sequencing and confirmed by Sanger sequencing, occurred in highly conserved regions of the protein in mammals. The parents were confirmed to be carriers. The variants were found at a low frequency in the 1000 Genomes Project and dbSNP databases. Functional studies were not performed.

.0007 MYOPATHY, MITOCHONDRIAL, AND ATAXIA, AUTOSOMAL RECESSIVE
MSTO1, IVS10AS, G-A, -1

For discussion of the c.1099-1G-A mutation in intron 10 of the MSTO1 gene that was identified in compound heterozygous state in a patient with autosomal recessive mitochondrial myopathy and ataxia (MMYAT; 617675) by Iwama et al. (2018), see 617619.0006.

.0008 MYOPATHY, MITOCHONDRIAL, AND ATAXIA, AUTOSOMAL RECESSIVE
MSTO1, GLN27TER

For discussion of the c.79C-T transition in the MSTO1 gene, resulting in a gln27-to-ter substitution, that was identified in compound heterozygous state in a patient with autosomal recessive mitochondrial myopathy and ataxia (MMYAT; 617675) by Iwama et al. (2018), see 617619.0006.

.0009 MYOPATHY, MITOCHONDRIAL, AND ATAXIA, AUTOSOMAL RECESSIVE
MSTO1, 1-BP DEL, 1259G

For discussion of the 1-bp deletion (c.1259delG, NM_018116.3) in the MSTO1 gene that was found in compound heterozygous state in sibs with autosomal recessive mitochondrial myopathy and ataxia (MMYAT; 617675) by Li et al. (2020), see 617619.0006.

Tags: 1q22