HGNC Approved Gene Symbol: MATN3
SNOMEDCT: 715674008, 719166003;
Cytogenetic location: 2p24.1 Genomic coordinates (GRCh38) : 2:19,992,052-20,012,668 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p24.1 | {Osteoarthritis susceptibility 2} | 140600 | Autosomal dominant | 3 |
| Epiphyseal dysplasia, multiple, 5 | 607078 | Autosomal dominant | 3 | |
| Spondyloepimetaphyseal dysplasia, Borochowitz-Cormier-Daire type | 608728 | Autosomal recessive | 3 |
Matrilin-3 (MATN3) is a member of family of extracellular matrix proteins that contain von Willebrand factor (VWF; 613160) type A (VWFA)-like domains (Wagener et al., 1997). For background information on matrilins, see MATN1 (115437).
Wagener et al. (1997) reported on the deduced primary structure of matrilin-3 from mouse, which is highly homologous to matrilin-1 and -2 (602108) but differs from both by lacking the second VWFA-like domain. The investigators also reported the partial sequence of a putative human matrilin-3 homolog.
Belluoccio et al. (1998) isolated a cDNA clone for human MATN3 from a cartilage-specific cDNA library. The MATN3 cDNA encodes a predicted 486-amino acid protein that shares 83% identity with the mouse protein. By Northern blot analysis, MATN3 was detected as a 2.8-kb mRNA in all cartilaginous tissues tested, but was not detected in any noncartilaginous tissues. It was also produced in vitro by primary chondrocytes isolated from articular cartilage; however, dedifferentiated chondrocytes of the third passage did not express any MATN3.
By fluorescence in situ hybridization, Belluoccio et al. (1998) mapped the human MATN3 gene to chromosome 2p24-p23.
Wagener et al. (2000) mapped the mouse Matn3 gene to the proximal end of chromosome 12, linked to the genes Synd1 (186355), Apob (107730), Dtnb (602415), and Kif3c (602845). The human homologs of all 5 of these genes map to 2p23, indicating considerable homology of synteny.
Multiple Epiphyseal Dysplasia 5
Chapman et al. (2001) performed a genomewide screen of a 4-generation family with an autosomal dominant form of multiple epiphyseal dysplasia (MED) not linked to COMP (600310), COL9A2 (120260), or COL9A3 (120270), respectively, and found significant genetic evidence for an MED locus on the short arm of chromosome 2 at 2p24-p23. Matrilin-3 was found in the critical region. In 2 unrelated families with multiple epiphyseal dysplasia-5 (EDM5; 607078), Chapman et al. (2001) identified 2 different missense mutations in the exon encoding the VWFA domain of matrilin-3: val194 to asp (V194D; 602109.0001) and arg121 to trp (R121W; 602109.0002). These were the first mutations to be identified in any of the genes encoding the matrilin family of proteins and confirmed a role for matrilin-3 in the development and homeostasis of cartilage and bone. Since Aszodi et al. (1999) found no phenotype in mice deficient in matrilin-1, Chapman et al. (2001) suggested that the pathogenic mechanism of MED caused by mutation in matrilin-3 may be mediated by a dominant-negative effect.
In affected members of 7 families with multiple epiphyseal dysplasia, Jackson et al. (2004) identified 4 novel mutations (see, e.g., 602109.0004; 602109.0008-602109.0009) and 1 recurrent mutation (R121W; 602109.0002) in the MATN3 gene. All of the disease-causing mutations were located within the beta sheet of the VWFA domain of matrilin-3, which strongly suggested that they have a deleterious effect on the folding and/or function of matrilin-3.
Otten et al. (2005) introduced 3 point mutations into the mouse Matn3 gene resulting in the substitutions R116W, T298M, and C299S, corresponding to the human disease-causing mutations R121W (602109.0002), T303M (602109.0003), and C304S (602109.0005), respectively. The chondrodysplasia (see 607078)-linked mutants R116W and C299S were poorly expressed and hardly detectable in supernatants of transiently transfected cells; immunofluorescence revealed that R116W and C299S were retained and accumulated in the endoplasmic reticulum. In contrast, the T298M mutation, corresponding to a mutation linked to hand arthritis (140600), did not appear to interfere with protein trafficking. In cells transfected with wildtype and T298M constructs, a Matn3-containing filamentous network was formed around the cells, whereas in cells with R116W and C299S, such structures were completely absent.
Cotterill et al. (2005) expressed wildtype and mutant MATN3 (e.g., 602109.0001 and 602109.0002) in Chinese hamster ovary cells and observed that wildtype matrilin-3 was efficiently secreted into the conditioned medium, whereas mutant matrilin-3 was retained and accumulated within the cell. When the mutant VWFA domains were examined individually, they existed primarily in an unfolded conformation. Light microscopy of cartilage from a MED patient with an R121W mutation showed the presence of intracellular material within the chondrocytes, while the overall matrix appeared normal. On electron micrographs, the inclusions noted at the light microscopy level appeared to be dilated cisternae of rough endoplasmic reticulum, and immunohistochemical analysis confirmed that the retained protein was matrilin-3. Cotterill et al. (2005) concluded that MED caused by MATN3 mutations is the result of an intracellular retention of the mutant protein.
Maeda et al. (2005) noted that previous reports regarding more than 18 families with MED indicated that MATN3 mutations in MED are confined to exon 2, which encodes the VWFA domain. Maeda et al. (2005) reported a novel MATN3 mutation outside the VWFA domain (602109.0006) in a 32-year-old patient with MED.
Using targeted copy number variant screening, Pettersson et al. (2018) identified a de novo heterozygous tandem duplication of exons 2 to 5 in the MATN3 gene (602109.0010) in a girl with EDM5. Sequencing and breakpoint junction PCR indicated a tandem orientation, and the 10.4-kb duplication was shown to be Alu-mediated. The intragenic duplication was predicted to cause premature termination of the MATN3 protein, resulting in complete loss of the last 2 domains of the MATN3 protein.
Osteoarthritis Susceptibility 2
Among 2,162 Icelandic patients with hand osteoarthritis (140600), Stefansson et al. (2003) identified 43 patients who were heterozygous, and 2 who were homozygous, for a thr303-to-met mutation (T303M; 602109.0003) in the MATN3 gene. Among the patients, 1,312 had arthritis of the first carpometacarpal joints, 30 of whom had the T303M mutation.
Otten et al. (2005) found that a T298M mutation in mouse Matn3, corresponding to the T303M MATN3 mutation linked to hand arthritis, resulted in expression levels, processing, and secretion pattern similar to wildtype protein in primary articular chondrocytes, suggesting minimal effects on the structure and function of the protein. In cells transfected with wildtype and T298M constructs, a Matn3-containing filamentous network was formed around the cells.
Spondyloepimetaphyseal Dysplasia, Borochowitz-Cormier-Daire Type
In affected members of a family segregating spondyloepimetaphyseal dysplasia (SEMDBCD; 608728), Borochowitz et al. (2004) identified a homozygous mutation in the MATN3 gene (C304S; 602109.0005).
In a 22-month-old Indian child with SEMD, Shyamasundar et al. (2020) identified a homozygous missense mutation in the MATN3 gene (T120M; 602109.0008). The mutation, which was found by exome sequencing, was present in heterozygous state in the parents.
To assess the function of matrilin-3 during skeletal development, Ko et al. (2004) generated Matn3-null mice. Homozygous mutant mice appeared normal, were fertile, and showed no obvious skeletal malformations. Histologic and ultrastructural analysis revealed endochondral bone formation indistinguishable from that of wildtype animals. Northern blot, immunohistochemical, and biochemical analyses indicated no compensatory upregulation of any other member of the matrilin family. Ko et al. (2004) hypothesized that matrilins are functionally redundant and that the phenotypes of MED disorders are not caused by the absence of matrilin-3 in cartilage.
In a family segregating autosomal dominant multiple epiphyseal dysplasia (EDM5; 607078), Chapman et al. (2001) identified an A-to-T transversion at position 598 of the MATN3 gene which was predicted to result in a valine-to-aspartic acid substitution at codon 194 (V194D), within the von Willebrand factor A domain of matrilin-3. This mutation was present in all affected family members.
In a patient with multiple epiphyseal dysplasia (EDM5; 607078) and his affected father, Chapman et al. (2001) identified a C-to-T transition at position 378 of the MATN3 gene. This mutation results in an arg-to-trp substitution at codon 121, within the von Willebrand factor A domain of matrilin-3.
In affected members of 3 families with multiple epiphyseal dysplasia, Jackson et al. (2004) identified the R121W mutation. The mutation was associated with marked interfamilial variability in the radiographic phenotype, suggesting that other genetic factors acted to modify the severity of the disorder in these patients.
Among 2,162 Icelandic patients with hand osteoarthritis (OS2; 140600), Stefansson et al. (2003) identified 43 patients who were heterozygous, and 2 who were homozygous, for a 47928C-T transition, designated SNP5, in the third exon of the MATN3 gene; the transition was nearly nonexistent in 873 control subjects and caused a thr303-to-met (T303M) mutation in the first epidermal growth factor (EGF) domain of the protein. Among the patients, 1,312 had arthritis of the first carpometacarpal joints, 30 of whom had the T303M mutation. The estimated relative risk of hand osteoarthritis for carriers of a single copy of the mutation as compared to noncarriers was estimated at 2.12.
In a family in which members of 3 successive generations had multiple epiphyseal dysplasia (EDM5; 607078), Jackson et al. (2004) identified a heterozygous 656C-A transversion in exon 2 of the MATN3 gene, resulting in an ala219-to-asp (A219D) mutation. The proband in the third generation carried an E252K nonsynonymous change that was thought to be a polymorphism, located on the other chromosome from the A219D mutation. The polymorphism, presumably inherited from the unaffected father, may have resulted in a more severe phenotype in the proband than in the 2 previous generations.
In affected members of a large consanguineous Arab Muslim family with autosomal recessive spondyloepimetaphyseal dysplasia (SEMDBCD; 608728), Borochowitz et al. (2004) identified a homozygous 973T-to-A transversion in the MATN3 gene, predicting a cys304-to-ser (C304S) substitution in the first EGF domain of MATN3. Heterozygotes in the family had no clinical or radiographic abnormalities.
In a patient with multiple epiphyseal dysplasia (EDM5; 607078), Maeda et al. (2005) identified a 209G-A transition, resulting in an arg70-to-his (R70H) substitution in exon 1 of the MATN3 gene. They pointed out that the arg70 residue is outside the von Willebrand factor A domain, suggesting that a mutation in the VWFA domain is not always a prerequisite for the MATN3 mutation in MED.
In affected members of a large Dutch family with autosomal dominant multiple epiphyseal dysplasia (EDM5; 607078) originally reported by Elsbach (1959), Mostert et al. (2003) identified heterozygosity for a 382G-T transversion in exon 2 of the MATN3 gene, resulting in an ala123-to-pro (A128P) substitution within the VWFA domain.
Multiple Epiphyseal Dysplasia 5
In an 8-year-old girl (family 3) with multiple epiphyseal dysplasia-5 (EDM5; 607078), Jackson et al. (2004) identified compound heterozygous mutations in the MATN3 gene: c.359C-T transition in exon 2, predicted to result in a thr120-to-met (T120M) substitution, and a c.908C-T transition in exon 3, predicted to result in a thr303-to-met (T303M; 602109.0009) substitution. Analysis of DNA from her apparently unaffected mother demonstrated the presence of T120M but not T303M. The father's DNA was not available for study.
Spondyloepimetaphyseal Dysplasia, Borochowitz-Cormier-Daire Type
In a 22-month-old Indian child with spondyloepimetaphyseal dysplasia of the Borochowitz-Cormier-Daire type (SEMDBCD; 608728), Shyamasundar et al. (2020) identified a homozygous c.359C-T transition in exon 2 of the MATN3 gene, resulting in a thr120-to-met (T120M) substitution. The mutation, which was found by exome sequencing, was present in heterozygous state in the parents. The mutation is located in the beta sheet of the single-A domain of matrilin-3, which suggests a deleterious effect on the folding and function of the protein.
For discussion of the c.908C-T transition in exon 3 of the MATN3 gene, predicted to result in a thr303-to-met (T303M) substitution, that was found in compound heterozygous state in a patient with multiple epiphyseal dysplasia-5 (EDM5; 607078) by Jackson et al. (2004), see 602109.0008.
In a girl with multiple epiphyseal dysplasia-5 (EDM5; 607078), Pettersson et al. (2018) identified heterozygosity for a de novo 10.4-kb intragenic tandem duplication (chr2.20,198,536-20,208,996dup, GRCh37) of exons 2 to 5 in the MATN3 gene. The duplication was predicted to cause premature termination of the MATN3 protein, resulting in complete loss of the last 2 domains of the protein. No patient fibroblasts were available for study.
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Shyamasundar, L. G., Loganathan, L., Kumar, A., Selina, A., Madhuri, V. MATN3 mutation causing spondyloepimetaphyseal dysplasia. (Letter) Indian J. Pediat. 87: 227-228, 2020. [PubMed: 31724101] [Full Text: https://doi.org/10.1007/s12098-019-03100-5]
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