* 617619

MISATO MITOCHONDRIAL DISTRIBUTION AND MORPHOLOGY REGULATOR 1; MSTO1


Alternative titles; symbols

MISATO 1, MITOCHONDRIAL DISTRIBUTION AND MORPHOLOGY REGULATOR
MISATO, DROSOPHILA, HOMOLOG OF


HGNC Approved Gene Symbol: MSTO1

Cytogenetic location: 1q22     Genomic coordinates (GRCh38): 1:155,563,246-155,614,967 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
1q22 Myopathy, mitochondrial, and ataxia 617675 AD, AR 3

TEXT

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).

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.

Donkervoort et al. (2019) reported homozygous or compound heterozygous mutations in the MSTO1 gene in 14 patients from 11 families with MMYAT; in 1 patient (patient 9) from a twelfth family, only heterozygosity for a single mutation was identified (Y478C). The mutations included 10 missense mutations (see, e.g., 617619.0006 and 617619.0010), 1 frameshift mutation, and 2 deletions. MSTO1 protein expression was absent in fibroblasts in patients 3 through 9. Imaging of mitochondrial networks in the patient fibroblasts demonstrated mitochondrial fragmentation, depletion of mtDNA, abnormalities in mtDNA nucleoid size and number, and enlarged lysosomes.

Reclassified Variants

The V8M mutation (617619.0005) reported by Gal et al. (2017) as the cause of autosomal dominant mitochondrial myopathy and ataxia (MYMAT; 617675) has been reclassified as a variant of unknown significance. In a Hungarian woman and her 3 adult children with autosomal dominant mitochondrial myopathy and ataxia, Gal et al. (2017) identified a heterozygous c.22G-A transition 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.


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 ( 10 Selected Examples):

.0001 MYOPATHY, MITOCHONDRIAL, AND ATAXIA, AUTOSOMAL RECESSIVE

MSTO1, ARG345CYS (rs150075701)
  
RCV000505818

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
  
RCV000505815

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
  
RCV000505816...

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
  
RCV000505819...

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 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE

MSTO1, VAL8MET (rs762798018)
  
RCV000505814...

This variant, formerly titled MYOPATHY, MITOCHONDRIAL, AND ATAXIA, AUTOSOMAL DOMINANT, has been reclassified because Gal et al. (2023) published an erratum in which they retracted their claim that there was a direct link between this variant and the patients' myopathy and ataxia phenotypes.

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
  
RCV000768553...

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.

In 4 patients, including 3 sibs (family 1) and an unrelated patient (patient 11), with MMYAT, Donkervoort et al. (2019) identified compound heterozygous mutations in the MSTO1 gene: R279H and a c.706G-C transversion, resulting in an asp236-to-his (D236H; 617619.0010) substitution. The mutations were identified by whole-exome sequencing and segregated with disease in the family. The authors noted that the D279H mutation was reported in the gnomAD database at an allele frequency of 0.00026 but with 1 homozygote reported, and in the ExAC database with an allele frequency of 0.00019. MSTO1 protein expression was absent in fibroblasts from one of the sibs.


.0007 MYOPATHY, MITOCHONDRIAL, AND ATAXIA, AUTOSOMAL RECESSIVE

MSTO1, IVS10AS, G-A, -1
  
RCV001269342

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
  
RCV001269343

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
  
RCV000598557...

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.


.0010 MYOPATHY, MITOCHONDRIAL, AND ATAXIA, AUTOSOMAL RECESSIVE

MSTO1, ASP236HIS
  
RCV001254689...

For discussion of the c.706G-C transversion (c.706G-C, NM_018116.3) in the MSTO1 gene, resulting in an asp236-to-his (D236H) substitution, that was found in compound heterozygous state in 3 sibs and an unrelated patient with mitochondrial myopathy and ataxia (MMYAT; 617675) by Donkervoort et al. (2019), see 617619.0006.


REFERENCES

  1. Donkervoort, S., Sabouny, R., Yun, P., Gauquelin, L., Chao, K. R., Hu, Y., Al Khatib, I., Topf, A., Mohassel, P., Cummings, B. B., Kaur, R., Saade, D., and 37 others. MSTO1 mutations cause mtDNA depletion, manifesting as muscular dystrophy with cerebellar involvement. Acta Neuropath. 138: 1013-1031, 2019. [PubMed: 31463572, images, related citations] [Full Text]

  2. Gal, A., Balicza, P., Weaver, D., Naghdi, S., Joseph, S. K., Varnai, P., Gyuris, T., Horvath, A., Nagy, L., Seifert, E. L., Molnar, J. J., Hajnoczky, G. MSTO1 is a cytoplasmic pro-mitochondrial fusion protein, whose mutation induces myopathy and ataxia in humans. EMBO Molec. Med. 9: 967-984, 2017. Note: Erratum: 15: e17911, 2023. [PubMed: 28554942, images, related citations] [Full Text]

  3. Gal, A., Balicza, P., Weaver, D., Naghdi, S., Joseph, S. K., Varnai, P., Gyuris, T., Horvath, A., Nagy, L., Seifert, E. L., Molnar, M. J., Hajnoczky, G. MSTO1 is a cytoplasmic pro-mitochondrial fusion protein, whose mutation induces myopathy and ataxia in humans. EMBO Molec. Med. 15: e17911, 2023. Note: Erratum. [PubMed: 37431817, related citations] [Full Text]

  4. Iwama, K., Takaori, T., Fukushima, A., Tohyama, J., Ishiyama, A., Ohba, C., Mitsuhashi, S., Miyatake, S., Takata, A., Miyake, N., Ito, S., Saitsu, H., Mizuguchi, T., Matsumoto, N. Novel recessive mutations in MSTO1 cause cerebellar atrophy with pigmentary retinopathy. J. Hum. Genet. 63: 263-270, 2018. [PubMed: 29339779, related citations] [Full Text]

  5. Kimura, M., Okano, Y. Human Misato regulates mitochondrial distribution and morphology. Exp. Cell Res. 313: 1393-1404, 2007. [PubMed: 17349998, related citations] [Full Text]

  6. Li, K., Jin, R., Wu, X. Whole-exome sequencing identifies rare compound heterozygous mutations in the MSTO1 gene associated with cerebellar ataxia and myopathy. Europ. J. Med. Genet. 63: 103623, 2020. Note: Electronic Article. [PubMed: 30684668, related citations] [Full Text]

  7. Miklos, G. L., Yamamoto, M.-T., Burns, R. G., Maleszka, R. An essential cell division gene of Drosophila, absent from Saccharomyces, encodes an unusual protein with tubulin-like and myosin-like peptide motifs. Proc. Nat. Acad. Sci. 94: 5189-5194, 1997. [PubMed: 9144213, images, related citations] [Full Text]

  8. Nasca, A., Scotton, C., Zaharieva, I., Neri, M., Selvatici, R., Magnusson, O. T., Gal, A., Weaver, D., Rossi, R., Armaroli, A., Pane, M., Phadke, R., and 10 others. Recessive mutations in MSTO1 cause mitochondrial dynamics impairment, leading to myopathy and ataxia. Hum. Mutat. 38: 970-977, 2017. [PubMed: 28544275, images, related citations] [Full Text]


Hilary J. Vernon - updated : 11/09/2022
Hilary J. Vernon - updated : 12/03/2020
Cassandra L. Kniffin - updated : 09/19/2017
Creation Date:
Patricia A. Hartz : 08/10/2017
alopez : 01/26/2024
carol : 08/28/2023
carol : 11/30/2022
carol : 11/11/2022
carol : 11/10/2022
carol : 11/09/2022
carol : 12/03/2020
carol : 09/22/2017
ckniffin : 09/19/2017
mgross : 08/10/2017

* 617619

MISATO MITOCHONDRIAL DISTRIBUTION AND MORPHOLOGY REGULATOR 1; MSTO1


Alternative titles; symbols

MISATO 1, MITOCHONDRIAL DISTRIBUTION AND MORPHOLOGY REGULATOR
MISATO, DROSOPHILA, HOMOLOG OF


HGNC Approved Gene Symbol: MSTO1

Cytogenetic location: 1q22     Genomic coordinates (GRCh38): 1:155,563,246-155,614,967 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
1q22 Myopathy, mitochondrial, and ataxia 617675 Autosomal dominant; Autosomal recessive 3

TEXT

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).

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.

Donkervoort et al. (2019) reported homozygous or compound heterozygous mutations in the MSTO1 gene in 14 patients from 11 families with MMYAT; in 1 patient (patient 9) from a twelfth family, only heterozygosity for a single mutation was identified (Y478C). The mutations included 10 missense mutations (see, e.g., 617619.0006 and 617619.0010), 1 frameshift mutation, and 2 deletions. MSTO1 protein expression was absent in fibroblasts in patients 3 through 9. Imaging of mitochondrial networks in the patient fibroblasts demonstrated mitochondrial fragmentation, depletion of mtDNA, abnormalities in mtDNA nucleoid size and number, and enlarged lysosomes.

Reclassified Variants

The V8M mutation (617619.0005) reported by Gal et al. (2017) as the cause of autosomal dominant mitochondrial myopathy and ataxia (MYMAT; 617675) has been reclassified as a variant of unknown significance. In a Hungarian woman and her 3 adult children with autosomal dominant mitochondrial myopathy and ataxia, Gal et al. (2017) identified a heterozygous c.22G-A transition 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.


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 10 Selected Examples):

.0001   MYOPATHY, MITOCHONDRIAL, AND ATAXIA, AUTOSOMAL RECESSIVE

MSTO1, ARG345CYS ({dbSNP rs150075701})
SNP: rs749922789, gnomAD: rs749922789, ClinVar: RCV000505818

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
SNP: rs1553295536, ClinVar: RCV000505815

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
SNP: rs622288, gnomAD: rs622288, ClinVar: RCV000505816, RCV001266925, RCV001788237

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
SNP: rs771965165, gnomAD: rs771965165, ClinVar: RCV000505819, RCV001591151

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   RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE

MSTO1, VAL8MET ({dbSNP rs762798018})
SNP: rs762798018, gnomAD: rs762798018, ClinVar: RCV000505814, RCV003228940

This variant, formerly titled MYOPATHY, MITOCHONDRIAL, AND ATAXIA, AUTOSOMAL DOMINANT, has been reclassified because Gal et al. (2023) published an erratum in which they retracted their claim that there was a direct link between this variant and the patients' myopathy and ataxia phenotypes.

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
SNP: rs563943670, gnomAD: rs563943670, ClinVar: RCV000768553, RCV001816791

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.

In 4 patients, including 3 sibs (family 1) and an unrelated patient (patient 11), with MMYAT, Donkervoort et al. (2019) identified compound heterozygous mutations in the MSTO1 gene: R279H and a c.706G-C transversion, resulting in an asp236-to-his (D236H; 617619.0010) substitution. The mutations were identified by whole-exome sequencing and segregated with disease in the family. The authors noted that the D279H mutation was reported in the gnomAD database at an allele frequency of 0.00026 but with 1 homozygote reported, and in the ExAC database with an allele frequency of 0.00019. MSTO1 protein expression was absent in fibroblasts from one of the sibs.


.0007   MYOPATHY, MITOCHONDRIAL, AND ATAXIA, AUTOSOMAL RECESSIVE

MSTO1, IVS10AS, G-A, -1
SNP: rs745944305, gnomAD: rs745944305, ClinVar: RCV001269342

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
SNP: rs1673545403, ClinVar: RCV001269343

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
SNP: rs1248439783, gnomAD: rs1248439783, ClinVar: RCV000598557, RCV000768552

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.


.0010   MYOPATHY, MITOCHONDRIAL, AND ATAXIA, AUTOSOMAL RECESSIVE

MSTO1, ASP236HIS
SNP: rs753488873, gnomAD: rs753488873, ClinVar: RCV001254689, RCV001786458

For discussion of the c.706G-C transversion (c.706G-C, NM_018116.3) in the MSTO1 gene, resulting in an asp236-to-his (D236H) substitution, that was found in compound heterozygous state in 3 sibs and an unrelated patient with mitochondrial myopathy and ataxia (MMYAT; 617675) by Donkervoort et al. (2019), see 617619.0006.


REFERENCES

  1. Donkervoort, S., Sabouny, R., Yun, P., Gauquelin, L., Chao, K. R., Hu, Y., Al Khatib, I., Topf, A., Mohassel, P., Cummings, B. B., Kaur, R., Saade, D., and 37 others. MSTO1 mutations cause mtDNA depletion, manifesting as muscular dystrophy with cerebellar involvement. Acta Neuropath. 138: 1013-1031, 2019. [PubMed: 31463572] [Full Text: https://doi.org/10.1007/s00401-019-02059-z]

  2. Gal, A., Balicza, P., Weaver, D., Naghdi, S., Joseph, S. K., Varnai, P., Gyuris, T., Horvath, A., Nagy, L., Seifert, E. L., Molnar, J. J., Hajnoczky, G. MSTO1 is a cytoplasmic pro-mitochondrial fusion protein, whose mutation induces myopathy and ataxia in humans. EMBO Molec. Med. 9: 967-984, 2017. Note: Erratum: 15: e17911, 2023. [PubMed: 28554942] [Full Text: https://doi.org/10.15252/emmm.201607058]

  3. Gal, A., Balicza, P., Weaver, D., Naghdi, S., Joseph, S. K., Varnai, P., Gyuris, T., Horvath, A., Nagy, L., Seifert, E. L., Molnar, M. J., Hajnoczky, G. MSTO1 is a cytoplasmic pro-mitochondrial fusion protein, whose mutation induces myopathy and ataxia in humans. EMBO Molec. Med. 15: e17911, 2023. Note: Erratum. [PubMed: 37431817] [Full Text: https://doi.org/10.15252/emmm.202317911]

  4. Iwama, K., Takaori, T., Fukushima, A., Tohyama, J., Ishiyama, A., Ohba, C., Mitsuhashi, S., Miyatake, S., Takata, A., Miyake, N., Ito, S., Saitsu, H., Mizuguchi, T., Matsumoto, N. Novel recessive mutations in MSTO1 cause cerebellar atrophy with pigmentary retinopathy. J. Hum. Genet. 63: 263-270, 2018. [PubMed: 29339779] [Full Text: https://doi.org/10.1038/s10038-017-0405-8]

  5. Kimura, M., Okano, Y. Human Misato regulates mitochondrial distribution and morphology. Exp. Cell Res. 313: 1393-1404, 2007. [PubMed: 17349998] [Full Text: https://doi.org/10.1016/j.yexcr.2007.02.004]

  6. Li, K., Jin, R., Wu, X. Whole-exome sequencing identifies rare compound heterozygous mutations in the MSTO1 gene associated with cerebellar ataxia and myopathy. Europ. J. Med. Genet. 63: 103623, 2020. Note: Electronic Article. [PubMed: 30684668] [Full Text: https://doi.org/10.1016/j.ejmg.2019.01.013]

  7. Miklos, G. L., Yamamoto, M.-T., Burns, R. G., Maleszka, R. An essential cell division gene of Drosophila, absent from Saccharomyces, encodes an unusual protein with tubulin-like and myosin-like peptide motifs. Proc. Nat. Acad. Sci. 94: 5189-5194, 1997. [PubMed: 9144213] [Full Text: https://doi.org/10.1073/pnas.94.10.5189]

  8. Nasca, A., Scotton, C., Zaharieva, I., Neri, M., Selvatici, R., Magnusson, O. T., Gal, A., Weaver, D., Rossi, R., Armaroli, A., Pane, M., Phadke, R., and 10 others. Recessive mutations in MSTO1 cause mitochondrial dynamics impairment, leading to myopathy and ataxia. Hum. Mutat. 38: 970-977, 2017. [PubMed: 28544275] [Full Text: https://doi.org/10.1002/humu.23262]


Contributors:
Hilary J. Vernon - updated : 11/09/2022
Hilary J. Vernon - updated : 12/03/2020
Cassandra L. Kniffin - updated : 09/19/2017

Creation Date:
Patricia A. Hartz : 08/10/2017

Edit History:
alopez : 01/26/2024
carol : 08/28/2023
carol : 11/30/2022
carol : 11/11/2022
carol : 11/10/2022
carol : 11/09/2022
carol : 12/03/2020
carol : 09/22/2017
ckniffin : 09/19/2017
mgross : 08/10/2017