* 164015

MATRIN 3; MATR3


HGNC Approved Gene Symbol: MATR3

Cytogenetic location: 5q31.2     Genomic coordinates (GRCh38): 5:139,273,751-139,331,676 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number		 Inheritance Phenotype
mapping key
5q31.2 Amyotrophic lateral sclerosis 21 606070 AD 3

TEXT

▼ Description

The MATR3 gene encodes a nuclear matrix protein that binds DNA and RNA (summary by Johnson et al., 2014).


▼ Cloning and Expression

Stuurman et al. (1990) showed that nuclear matrins, a group of proteins in the nuclear matrix, are present in cultured cells from a variety of tissues and are probably common to mammalian cells. Stuurman et al. (1990) differentiated 2 nuclear matrix fractions: the peripheral nuclear matrix (matrix proteins that remain insoluble after reduction), and the internal nuclear matrix (matrix proteins released by reduction).

Nakayasu and Berezney (1991) identified several novel nuclear matrins from a rat liver nuclear matrix and characterized them by peptide maps, polyclonal antibodies generated against the individual matrins, and indirect immunofluorescence microscopy. They designated the proteins matrins 3, 4, D-G, 12, and 13.

Belgrader et al. (1991) cloned a full-length rat insulinoma cDNA that encodes an acidic internal matrix protein designated matrin-3. The deduced 845-amino acid protein has a calculated molecular mass of approximately 95 kD. Its primary structure consists of 33% charged residues and is generally hydrophilic. Like the lamins (see 150330), matrin-3 has a positively charged N terminus that contains a large number of amino acids with free hydroxyl groups. A highly acidic domain near the C terminus, in which 32% of the amino acids are acidic, is a characteristic found in other nuclear proteins.

Nagase et al. (1998) cloned and sequenced matrin-3, which they called KIAA0723, from human brain cDNA libraries. The deduced protein contains 847 amino acids.


▼ Mapping

Using genomic sequence analysis, Senderek et al. (2009) mapped the MATR3 gene to chromosome 5q31.


▼ Gene Function

By immunohistochemistry, Johnson et al. (2014) detected MATR3 in a granular staining pattern in the nuclei of motor neurons and surrounding glial cells in human spinal cord sections. MATR3 interacted with TDP43 (TARDBP; 605078) in HEK293 cells.


▼ Molecular Genetics

In affected members of a North American family originally diagnosed with distal myopathy with vocal cord and pharyngeal weakness (Feit et al., 1998), but later reclassified as having amyotrophic lateral sclerosis (ALS21; 606070) (Johnson et al., 2014), Senderek et al. (2009) identified a heterozygous missense mutation in the MATR3 gene (S85C; 164015.0001). Senderek et al. (2009) found the same heterozygous mutation in an unrelated Bulgarian family with a similar disorder.

In affected members of a family of European ancestry with ALS21, Johnson et al. (2014) identified a heterozygous missense mutation in the MATR3 gene (F115C; 164015.0002). The mutation was found by exome sequencing. Most affected individuals in this family also had cognitive impairment or dementia. Exome sequence data from 108 additional familial ALS cases identified 1 heterozygous MATR3 missense mutation (T622A; 164015.0003) in an affected family. In addition, custom resequencing of genes linked to neurodegeneration in 96 British ALS cases identified a heterozygous mutation (P154S; 164015.0004) in a patient with sporadic disease. Immunohistochemical analysis of spinal cord section from a patient with the F115C mutation showed intense MATR3 immunoreactivity in the nucleus of all motor neurons and diffuse cytoplasmic staining in many neurons. Cytoplasmic inclusions were not present. Similar studies of spinal cord section from a patient with FTDALS (105550) due to the C9ORF72 repeat expansion (614260.0001) showed rare MATR3-positive cytoplasmic inclusions. MATR3 was also observed in the nuclei of remaining motor neurons and occasionally in the cytoplasm of spinal cord sections from non-MATR3 ALS. The findings suggested a role for aberrant RNA processing in motor neuron degeneration.


▼ ALLELIC VARIANTS ( 4 Selected Examples):

.0001  AMYOTROPHIC LATERAL SCLEROSIS 21

MATR3, SER85CYS   
dbSNP:rs121434591 RCV000015039...

In affected members of a North American family originally diagnosed with distal myopathy with vocal cord and pharyngeal weakness (Feit et al., 1998), but later reclassified as having amyotrophic lateral sclerosis (ALS21; 606070) (Johnson et al., 2014), Senderek et al. (2009) identified a heterozygous 254C-G transversion in exon 2 of the MATR3 gene, resulting in a ser85-to-cys (S85C) substitution. Senderek et al. (2009) found the same heterozygous mutation in an unrelated Bulgarian family with a similar disorder.

Johnson et al. (2014) found that the S85C mutation increased the interaction of mutant MATR3 with TARDBP (605078) compared to wildtype. S85C was also expressed at a lower steady-state level compared to wildtype and to other MATR3 variants, suggesting a structural effect of the mutation. Mutant S85C coaggregated with TARDBP in skeletal muscle from a patient carrying the mutation.

Muller et al. (2014) reported 16 patients from 6 unrelated German families with the S85C MATR3 mutation. Haplotype analysis indicated a founder effect that was distinct from the haplotype in the families reported by Johnson et al. (2014). Muller et al. (2014) concluded that the phenotype in the German families was more consistent with distal myopathy than ALS.


.0002  AMYOTROPHIC LATERAL SCLEROSIS 21

In affected members of a family of European ancestry with amyotrophic lateral sclerosis-21 (ALS21; 606070), Johnson et al. (2014) identified a heterozygous T-to-G transversion in the MATR3 gene, resulting in a phe115-to-cys (F115C) substitution. The mutation, which was found by exome sequencing, was not present in the Exome Sequencing Project or 1000 Genomes Project databases, in-house control chromosomes, or other controls (a total of 27,666 control chromosomes). In addition to upper and lower motor neurons signs, most affected individuals in this family also had cognitive impairment or dementia. The mutation did not affect MATR3 binding to TARDBP (605078). Immunohistochemical analysis of spinal cord section from a patient with the F115C mutation showed intense MATR3 immunoreactivity in the nucleus of all motor neurons and diffuse cytoplasmic staining in many neurons. Cytoplasmic inclusions were not present.


.0003  AMYOTROPHIC LATERAL SCLEROSIS 21

MATR3, THR622ALA   
dbSNP:rs587777301 RCV000114431

In 2 first cousins of Sardinian origin with amyotrophic lateral sclerosis-21 (ALS21; 606070), Johnson et al. (2014) identified a heterozygous A-to-G transition in the MATR3 gene, resulting in a thr622-to-ala (T622A) substitution. The mutation was found by examining exome sequence data of 108 familial ALS cases. The mutation was not present in 17,286 control chromosomes from public and in-house databases. The mutation did not affect MATR3 binding to TARDBP (605078).


.0004  AMYOTROPHIC LATERAL SCLEROSIS 21

MATR3, PRO154SER   
dbSNP:rs587777302 RCV000114432

In an Indian man with amyotrophic lateral sclerosis-21 (ALS21; 606070), Johnson et al. (2014) identified a heterozygous C-to-T transition in the MATR3 gene, resulting in a pro154-to-ser (P154S) substitution. The mutation was not present in 17,286 control chromosomes from public and in-house databases. There was no family history of the disorder. This patient was ascertained from a cohort of 96 British ALS patients. Functional studies of the variant were not performed.


▼ REFERENCES

  1. Belgrader, P., Dey, R., Berezney, R. Molecular cloning of matrin 3: a 125-kilodalton protein of the nuclear matrix contains an extensive acidic domain. J. Biol. Chem. 266: 9893-9899, 1991. [PubMed: 2033075, related citations] [Full Text]

  2. Feit, H., Silbergleit, A., Schneider, L. B., Gutierrez, J. A., Fitoussi, R.-P., Reyes, C., Rouleau, G. A., Brais, B., Jackson, C. E., Beckmann, J. S., Seboun, E. Vocal cord and pharyngeal weakness with autosomal dominant distal myopathy: clinical description and gene localization to 5q31. Am. J. Hum. Genet. 63: 1732-1742, 1998. [PubMed: 9837826, related citations] [Full Text]

  3. Johnson, J. O., Pioro, E. P., Boehringer, A., Chia, R., Feit, H., Renton, A. E., Pliner, H. A., Abramzon, Y., Marangi, G., Winborn, B. J., Gibbs, J.R., Nalls, M. A., and 30 others. Mutations in the matrin 3 gene cause familial amyotrophic lateral sclerosis. Nature Neurosci. 17: 664-666, 2014. [PubMed: 24686783, images, related citations] [Full Text]

  4. Muller, T. J., Kraya, T., Stoltenburg-Didinger, G., Hanisch, F., Kornhuber, M., Stoevesandt, D., Senderek, J., Weis, J., Baum, P., Deschauer, M., Zierz, S. Phenotype of matrin-3-related distal myopathy in 16 German patients. Ann. Neurol. 76: 669-680, 2014. [PubMed: 25154462, related citations] [Full Text]

  5. Nagase, T., Ishikawa, K., Suyama, M., Kikuno, R., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XI. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 5: 277-286, 1998. [PubMed: 9872452, related citations]

  6. Nakayasu, H., Berezney, R. Nuclear matrins: identification of the major nuclear matrix proteins. Proc. Nat. Acad. Sci. 88: 10312-10316, 1991. [PubMed: 1946450, related citations] [Full Text]

  7. Senderek, J., Garvey, S. M., Krieger, M., Guergueltcheva, V., Urtizberea, A., Roos, A., Elbracht, M., Stendel, C., Tournev, I., Mihailova, V., Feit, H., Tramonte, J., and 11 others. Autosomal-dominant distal myopathy associated with a recurrent missense mutation in the gene encoding the nuclear matrix protein, matrin 3. Am. J. Hum. Genet. 84: 511-518, 2009. [PubMed: 19344878, images, related citations] [Full Text]

  8. Stuurman, N., Meijne, A. M. L., van der Pol, A. J., de Jong, L., van Driel, R., van Renswoude, J. The nuclear matrix from cells of different origin: evidence for a common set of matrix proteins. J. Biol. Chem. 265: 5460-5465, 1990. [PubMed: 2180926, related citations] [Full Text]


Contributors:
Cassandra L. Kniffin - updated : 4/1/2015
Cassandra L. Kniffin - updated : 4/14/2014
Anne M. Stumpf - updated : 10/20/2009
Creation Date:
Victor A. McKusick : 11/27/1991
Edit History:
carol : 04/02/2015
mcolton : 4/1/2015
ckniffin : 4/1/2015
mcolton : 8/12/2014
carol : 4/15/2014
carol : 4/15/2014
mcolton : 4/14/2014
ckniffin : 4/14/2014
wwang : 7/1/2011
alopez : 10/20/2009
carol : 5/4/2007
supermim : 3/16/1992
carol : 11/27/1991

* 164015

MATRIN 3; MATR3


HGNC Approved Gene Symbol: MATR3

Cytogenetic location: 5q31.2     Genomic coordinates (GRCh38): 5:139,273,751-139,331,676 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number		 Inheritance Phenotype
mapping key
5q31.2 Amyotrophic lateral sclerosis 21 606070 Autosomal dominant 3

TEXT

Description

The MATR3 gene encodes a nuclear matrix protein that binds DNA and RNA (summary by Johnson et al., 2014).


Cloning and Expression

Stuurman et al. (1990) showed that nuclear matrins, a group of proteins in the nuclear matrix, are present in cultured cells from a variety of tissues and are probably common to mammalian cells. Stuurman et al. (1990) differentiated 2 nuclear matrix fractions: the peripheral nuclear matrix (matrix proteins that remain insoluble after reduction), and the internal nuclear matrix (matrix proteins released by reduction).

Nakayasu and Berezney (1991) identified several novel nuclear matrins from a rat liver nuclear matrix and characterized them by peptide maps, polyclonal antibodies generated against the individual matrins, and indirect immunofluorescence microscopy. They designated the proteins matrins 3, 4, D-G, 12, and 13.

Belgrader et al. (1991) cloned a full-length rat insulinoma cDNA that encodes an acidic internal matrix protein designated matrin-3. The deduced 845-amino acid protein has a calculated molecular mass of approximately 95 kD. Its primary structure consists of 33% charged residues and is generally hydrophilic. Like the lamins (see 150330), matrin-3 has a positively charged N terminus that contains a large number of amino acids with free hydroxyl groups. A highly acidic domain near the C terminus, in which 32% of the amino acids are acidic, is a characteristic found in other nuclear proteins.

Nagase et al. (1998) cloned and sequenced matrin-3, which they called KIAA0723, from human brain cDNA libraries. The deduced protein contains 847 amino acids.


Mapping

Using genomic sequence analysis, Senderek et al. (2009) mapped the MATR3 gene to chromosome 5q31.


Gene Function

By immunohistochemistry, Johnson et al. (2014) detected MATR3 in a granular staining pattern in the nuclei of motor neurons and surrounding glial cells in human spinal cord sections. MATR3 interacted with TDP43 (TARDBP; 605078) in HEK293 cells.


Molecular Genetics

In affected members of a North American family originally diagnosed with distal myopathy with vocal cord and pharyngeal weakness (Feit et al., 1998), but later reclassified as having amyotrophic lateral sclerosis (ALS21; 606070) (Johnson et al., 2014), Senderek et al. (2009) identified a heterozygous missense mutation in the MATR3 gene (S85C; 164015.0001). Senderek et al. (2009) found the same heterozygous mutation in an unrelated Bulgarian family with a similar disorder.

In affected members of a family of European ancestry with ALS21, Johnson et al. (2014) identified a heterozygous missense mutation in the MATR3 gene (F115C; 164015.0002). The mutation was found by exome sequencing. Most affected individuals in this family also had cognitive impairment or dementia. Exome sequence data from 108 additional familial ALS cases identified 1 heterozygous MATR3 missense mutation (T622A; 164015.0003) in an affected family. In addition, custom resequencing of genes linked to neurodegeneration in 96 British ALS cases identified a heterozygous mutation (P154S; 164015.0004) in a patient with sporadic disease. Immunohistochemical analysis of spinal cord section from a patient with the F115C mutation showed intense MATR3 immunoreactivity in the nucleus of all motor neurons and diffuse cytoplasmic staining in many neurons. Cytoplasmic inclusions were not present. Similar studies of spinal cord section from a patient with FTDALS (105550) due to the C9ORF72 repeat expansion (614260.0001) showed rare MATR3-positive cytoplasmic inclusions. MATR3 was also observed in the nuclei of remaining motor neurons and occasionally in the cytoplasm of spinal cord sections from non-MATR3 ALS. The findings suggested a role for aberrant RNA processing in motor neuron degeneration.


ALLELIC VARIANTS 4 Selected Examples):

.0001  AMYOTROPHIC LATERAL SCLEROSIS 21

MATR3, SER85CYS    rs121434591

In affected members of a North American family originally diagnosed with distal myopathy with vocal cord and pharyngeal weakness (Feit et al., 1998), but later reclassified as having amyotrophic lateral sclerosis (ALS21; 606070) (Johnson et al., 2014), Senderek et al. (2009) identified a heterozygous 254C-G transversion in exon 2 of the MATR3 gene, resulting in a ser85-to-cys (S85C) substitution. Senderek et al. (2009) found the same heterozygous mutation in an unrelated Bulgarian family with a similar disorder.

Johnson et al. (2014) found that the S85C mutation increased the interaction of mutant MATR3 with TARDBP (605078) compared to wildtype. S85C was also expressed at a lower steady-state level compared to wildtype and to other MATR3 variants, suggesting a structural effect of the mutation. Mutant S85C coaggregated with TARDBP in skeletal muscle from a patient carrying the mutation.

Muller et al. (2014) reported 16 patients from 6 unrelated German families with the S85C MATR3 mutation. Haplotype analysis indicated a founder effect that was distinct from the haplotype in the families reported by Johnson et al. (2014). Muller et al. (2014) concluded that the phenotype in the German families was more consistent with distal myopathy than ALS.


.0002  AMYOTROPHIC LATERAL SCLEROSIS 21

MATR3, PHE115CYS    rs587777300

In affected members of a family of European ancestry with amyotrophic lateral sclerosis-21 (ALS21; 606070), Johnson et al. (2014) identified a heterozygous T-to-G transversion in the MATR3 gene, resulting in a phe115-to-cys (F115C) substitution. The mutation, which was found by exome sequencing, was not present in the Exome Sequencing Project or 1000 Genomes Project databases, in-house control chromosomes, or other controls (a total of 27,666 control chromosomes). In addition to upper and lower motor neurons signs, most affected individuals in this family also had cognitive impairment or dementia. The mutation did not affect MATR3 binding to TARDBP (605078). Immunohistochemical analysis of spinal cord section from a patient with the F115C mutation showed intense MATR3 immunoreactivity in the nucleus of all motor neurons and diffuse cytoplasmic staining in many neurons. Cytoplasmic inclusions were not present.


.0003  AMYOTROPHIC LATERAL SCLEROSIS 21

MATR3, THR622ALA    rs587777301

In 2 first cousins of Sardinian origin with amyotrophic lateral sclerosis-21 (ALS21; 606070), Johnson et al. (2014) identified a heterozygous A-to-G transition in the MATR3 gene, resulting in a thr622-to-ala (T622A) substitution. The mutation was found by examining exome sequence data of 108 familial ALS cases. The mutation was not present in 17,286 control chromosomes from public and in-house databases. The mutation did not affect MATR3 binding to TARDBP (605078).


.0004  AMYOTROPHIC LATERAL SCLEROSIS 21

MATR3, PRO154SER    rs587777302

In an Indian man with amyotrophic lateral sclerosis-21 (ALS21; 606070), Johnson et al. (2014) identified a heterozygous C-to-T transition in the MATR3 gene, resulting in a pro154-to-ser (P154S) substitution. The mutation was not present in 17,286 control chromosomes from public and in-house databases. There was no family history of the disorder. This patient was ascertained from a cohort of 96 British ALS patients. Functional studies of the variant were not performed.


REFERENCES

  1. Belgrader, P., Dey, R., Berezney, R. Molecular cloning of matrin 3: a 125-kilodalton protein of the nuclear matrix contains an extensive acidic domain. J. Biol. Chem. 266: 9893-9899, 1991. [PubMed: 2033075] [Full Text: http://www.jbc.org/cgi/pmidlookup?view=long&pmid=2033075]

  2. Feit, H., Silbergleit, A., Schneider, L. B., Gutierrez, J. A., Fitoussi, R.-P., Reyes, C., Rouleau, G. A., Brais, B., Jackson, C. E., Beckmann, J. S., Seboun, E. Vocal cord and pharyngeal weakness with autosomal dominant distal myopathy: clinical description and gene localization to 5q31. Am. J. Hum. Genet. 63: 1732-1742, 1998. [PubMed: 9837826] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)61618-8]

  3. Johnson, J. O., Pioro, E. P., Boehringer, A., Chia, R., Feit, H., Renton, A. E., Pliner, H. A., Abramzon, Y., Marangi, G., Winborn, B. J., Gibbs, J.R., Nalls, M. A., and 30 others. Mutations in the matrin 3 gene cause familial amyotrophic lateral sclerosis. Nature Neurosci. 17: 664-666, 2014. [PubMed: 24686783] [Full Text: https://dx.doi.org/10.1038/nn.3688]

  4. Muller, T. J., Kraya, T., Stoltenburg-Didinger, G., Hanisch, F., Kornhuber, M., Stoevesandt, D., Senderek, J., Weis, J., Baum, P., Deschauer, M., Zierz, S. Phenotype of matrin-3-related distal myopathy in 16 German patients. Ann. Neurol. 76: 669-680, 2014. [PubMed: 25154462] [Full Text: https://doi.org/10.1002/ana.24255]

  5. Nagase, T., Ishikawa, K., Suyama, M., Kikuno, R., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XI. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 5: 277-286, 1998. [PubMed: 9872452]

  6. Nakayasu, H., Berezney, R. Nuclear matrins: identification of the major nuclear matrix proteins. Proc. Nat. Acad. Sci. 88: 10312-10316, 1991. [PubMed: 1946450] [Full Text: http://www.pnas.org/cgi/pmidlookup?view=long&pmid=1946450]

  7. Senderek, J., Garvey, S. M., Krieger, M., Guergueltcheva, V., Urtizberea, A., Roos, A., Elbracht, M., Stendel, C., Tournev, I., Mihailova, V., Feit, H., Tramonte, J., and 11 others. Autosomal-dominant distal myopathy associated with a recurrent missense mutation in the gene encoding the nuclear matrix protein, matrin 3. Am. J. Hum. Genet. 84: 511-518, 2009. [PubMed: 19344878] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/S0002-9297(09)00103-7]

  8. Stuurman, N., Meijne, A. M. L., van der Pol, A. J., de Jong, L., van Driel, R., van Renswoude, J. The nuclear matrix from cells of different origin: evidence for a common set of matrix proteins. J. Biol. Chem. 265: 5460-5465, 1990. [PubMed: 2180926] [Full Text: http://www.jbc.org/cgi/pmidlookup?view=long&pmid=2180926]


Contributors:
Cassandra L. Kniffin - updated : 4/1/2015
Cassandra L. Kniffin - updated : 4/14/2014
Anne M. Stumpf - updated : 10/20/2009
Creation Date:
Victor A. McKusick : 11/27/1991
Edit History:
carol : 04/02/2015
mcolton : 4/1/2015
ckniffin : 4/1/2015
mcolton : 8/12/2014
carol : 4/15/2014
carol : 4/15/2014
mcolton : 4/14/2014
ckniffin : 4/14/2014
wwang : 7/1/2011
alopez : 10/20/2009
carol : 5/4/2007
supermim : 3/16/1992
carol : 11/27/1991