HGNC Approved Gene Symbol: MATR3
Cytogenetic location: 5q31.2 Genomic coordinates (GRCh38): 5:139,274,101-139,331,677 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q31.2 | Amyotrophic lateral sclerosis 21 | 606070 | Autosomal dominant | 3 |
The MATR3 gene encodes a nuclear matrix protein that binds DNA and RNA (summary by Johnson et al., 2014).
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.
Using genomic sequence analysis, Senderek et al. (2009) mapped the MATR3 gene to chromosome 5q31.
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.
Amyotrophic Lateral Sclerosis 21
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.
Associations Pending Confirmation
For discussion of a possible association between variation in the MATR3 gene and an infantile-onset neurodegenerative disorder, see 164015.0005.
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.
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.
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).
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.
This variant is classified as a variant of unknown significance because its contribution to an infantile-onset neurodegenerative disorder has not been confirmed.
In a 2-year-old boy, born of unrelated Romanian parents, with an infantile-onset neurodegenerative disorder, Zech et al. (2021) identified a de novo heterozygous c.1306G-A transition (c.1306G-A, NM_018834.6) in exon 7 of the MATR3 gene, resulting in a glu436-to-lys (E436K) substitution in the first of 2 central RNA-recognition motifs. The variant, which was found by whole-exome sequencing, was not present in the gnomAD database. Immunoblot analysis of patient cells showed a 50% reduction in MATR3 protein levels compared to controls, consistent with haploinsufficiency. Further studies did not show abnormal localization or aggregation of MATR3 in patient cells. The patient presented soon after birth with hypotonia and feeding problems requiring tube feeding, and developed refractory seizures at 2 months of age. At 2 years, he had profoundly impaired development with microcephaly (Z score of -5.72), hypotonia with inability to move independently, lack of speech development, dystonic movements, and brisk reflexes. Brain imaging showed brain atrophy, delayed myelination, and hypoplasia of the corpus callosum.
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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://doi.org/10.1086/302166]
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://doi.org/10.1038/nn.3688]
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]
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] [Full Text: https://doi.org/10.1093/dnares/5.5.277]
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: https://doi.org/10.1073/pnas.88.22.10312]
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://doi.org/10.1016/j.ajhg.2009.03.006]
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]
Zech, M., Seibt, A., Zumbaum, B., Klee, D., Meitinger, T., Winkelmann, J., Mayatepek, E., Wagner, M., Distelmaier, F. MATR3 haploinsufficiency and early-onset neurodegeneration. Brain 144: e72, 2021. Note: Erratum: Brain: awab325, 2021. [PubMed: 34173818] [Full Text: https://doi.org/10.1093/brain/awab240]