Alternative titles; symbols
HGNC Approved Gene Symbol: MASP1
Cytogenetic location: 3q27.3 Genomic coordinates (GRCh38): 3:187,217,282-187,291,737 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q27.3 | 3MC syndrome 1 | 257920 | Autosomal recessive | 3 |
The Ra-reactive factor (RARF) is a complement-dependent bactericidal factor that binds to the Ra and R2 polysaccharides expressed by certain enterobacteria. RARF activity is found in the sera of a diverse group of vertebrates, suggesting that it is an evolutionarily conserved mechanism to resist infection by these bacterial strains. RARF includes a 100-kD component, CRARF, also called MASP1 or p100, that was thought to activate the complement components C4 (C4F, 120820; C4S, 120810), C2 (613927), and C3 (120700). Subsequent work, however, separated MASP1 from MASP2 (605102) and showed that MASP1 activates C3 and C2, whereas MASP2 activates C4 and C2. The other component of RARF is mannan-binding lectin (154545), a plasma protein member of the complement system that binds to microbial carbohydrates and activates the MASPs. The MASPs then recruit C4 and C2 to generate the C3 convertase or directly activate C3 (summary by Takada et al., 1995 and Matsushita et al., 2000).
Takada et al. (1993) cloned a partial human CRARF cDNA from a liver library. The human CRARF amino acid sequence is similar to the human complement subcomponents C1R (613785) and C1S (120580). Takada et al. (1995) obtained a corresponding mouse cDNA.
By RT-PCR with primers based on N-terminal peptide sequence analysis and the consensus sequence of serine proteases, followed by screening a fetal liver cDNA library, Sato et al. (1994) isolated a cDNA encoding MASP. Sequence analysis predicted that the 699-amino acid protein contains a leader peptide; 2 structural domains similar to those of C1R and C1S; an EGF-like domain thought to be related to calcium-binding activity; 2 short consensus repeat domains; and a serine protease domain. Northern blot analysis revealed expression of 4.8- and 3.4-kb MASP transcripts in fetal liver; no expression was detected in adult tissues or in fetal heart, brain, lung, or kidney. Sato et al. (1994) proposed that the MBL-MASP complex is a novel activator of complement in what they designated the lectin pathway.
By biochemical purification of plasma proteins and immunoblot analysis, Dahl et al. (2001) detected a 42-kD serine protease associated with MBL. They identified a cDNA encoding this protein, MASP3, which is generated by alternative splicing of MASP1. The MASP3 transcription product is composed of an A chain, which is common to both MASP1 and MASP3, and a B chain, which is unique to MASP3. The deduced 728-amino acid MASP3 protein has a signal peptide, 3 N-glycosylation sites on the B chain and 4 on the A chain.
Sirmaci et al. (2010) stated that the MASP1 gene encodes 3 isoforms; 2 isoforms (MASP1 and MASP3) contain different serine protease domains, and the third (MAp44) lacks a serine protease domain.
Dobo et al. (2009) determined the crystal structure of the catalytic region of MASP1 and refined it to 2.55-angstrom resolution. The structure contains a salt bridge and a long 60-loop. The width of the substrate-binding groove of MASP1 resembles trypsin (see 276000) rather than early complement proteases.
By analysis of genomic clones, Endo et al. (1996) found that the MASP1 catalytic domain is encoded by 6 exons. They proposed that the MASP1 gene is a prototype and that the intron-lacking sequences of C1S and C1R have a more recent history.
Takayama et al. (1999) determined that the MASP1 gene spans over 67 kb. It contains 10 exons encoding the nonprotease region of the protein, as in the case of C1R and C1S, and 6 exons encoding the serine protease region, in contrast to C1R and C1S, in which this region is encoded by a single exon.
By PCR with degenerate primers and by genomic sequence analysis, Dahl et al. (2001) determined that the unique MASP3 B chain is encoded by a single exon followed by a poly-A region between the 10 exons encoding the MASP1 A chain and the 6 exons encoding the MASP1 B chain.
Sato et al. (1994) mapped the MASP1 gene to 3q27-q28 by FISH. Using FISH, Takada et al. (1995) mapped the human CRARF gene to 3q27-q28 and the mouse gene to 16B2-B3, regions thought to share homology of synteny.
Matsushita et al. (2000) determined that MASP1 cleaves C3 and C2, while MASP2 cleaves C4 and C2 to generate the C3 convertase, C4BC2B. Both could be blocked by the C1 inhibitor (606860).
Rooryck et al. (2011) examined the effects of masp1 knockdown in zebrafish and observed pigment and craniofacial cartilage defects similar to those in colec11 (612502) morphants. Testing for epistasis by injection of suboptimal doses (below which no phenotype is seen when injected alone) of both colec11 and masp1 morpholinos into single-cell-stage zebrafish embryos showed that approximately 73% developed severe craniofacial abnormalities and some developed clefts in the ethmoid plate. These results suggested that the COLEC11 and MASP1 gene products function in the same pathway.
Degn et al. (2012) found that the alternative complement pathway functioned normally in a patient with 3MC syndrome (257920) and a trp290-to-ter (W290X; 600521.0005) mutation in the MASP1 gene, causing loss of the MASP1, MASP3, and MAp44 isoforms. Conversely, the patient had a nonfunctional lectin pathway that could be restored by MASP1. Degn et al. (2012) showed that MASP1 dramatically increased lectin pathway activity through direct activation of MASP2. Both MASP1 and MASP2 could associate in the same MBL complex, and this complex was present in human serum. Degn et al. (2012) concluded that MASP1 and MASP2 act in a manner analogous to C1R and C1S of the classical complement pathway.
In affected members of 2 Turkish families segregating 3MC syndrome mapping to chromosome 3q27 (3MC1; 257920), Sirmaci et al. (2010) performed whole genome sequencing of candidate genes and identified homozygosity for a missense and a nonsense mutation in the MASP1 gene (600521.0004-600521.0005, respectively).
In 2 families with 3MC syndrome mapping to chromosome 3q27, Rooryck et al. (2011) analyzed candidate genes and identified 2 homozygous missense mutations in the MASP1 gene (600521.0001 and 600521.0002, respectively). Analysis of the MASP1 gene in 2 additional Brazilian 3MC families revealed homozygosity for a third missense mutation in affected individuals (600521.0003). The mutations all occurred at well-conserved residues in exon 12 of the gene, segregated with the disorder in each family, and were not found in at least 506 ethnically matched control chromosomes.
In an affected male patient from a consanguineous Greek family with 3MC syndrome (3MC1; 257920), Rooryck et al. (2011) identified homozygosity for a 1489C-T transition in exon 12 of the MASP1 gene, resulting in a his497-to-tyr (H497Y) substitution at a highly conserved residue. The mutated alleles segregated with the disorder in the family and the mutation was not found in 572 northern European control chromosomes.
In 2 affected brothers from an Italian family with 3MC syndrome, (3MC1; 257920), Rooryck et al. (2011) identified homozygosity for a 1888T-C transition in exon 12 of the MASP1 gene, resulting in a cys630-to-arg (C630R) substitution at a highly conserved residue. The mutated alleles segregated with the disorder in the family and the mutation was not found in 506 North European control chromosomes.
In 3 affected individuals from 2 Brazilian families with 3MC syndrome, (3MC1; 257920), previously reported by Leal and Baptista (2007) and Leal et al. (2008), respectively, Rooryck et al. (2011) identified homozygosity for a 1997G-A transition in exon 12 of the MASP1 gene, resulting in a gly666-to-glu (G666E) substitution at a highly conserved residue. The mutated alleles segregated with the disorder in both families and the mutation was not found in 506 North European control chromosomes.
In 2 Turkish sisters with 3MC1 syndrome (257920), the offspring of first-cousin parents, Sirmaci et al. (2010) identified homozygosity for a 2059G-A transition in the MASP1 gene, resulting in a gly687-to-arg (G687R) substitution. The mutation occurred in an exon unique to the MASP3 isoform. Both parents and an unaffected sib were heterozygous for the mutation, which was not found in 2 healthy sibs or in 192 healthy Turkish controls or 1,200 controls of various other ancestries.
In a 9-year-old Turkish female with 3MC1 syndrome (257920), the offspring of first-cousin parents, Sirmaci et al. (2010) identified homozygosity for an 870G-A transition in the MASP1 gene, resulting in a trp290-to-ter (W290X) substitution. The mutation occurred in coding exon 6, which is shared by all MASP1 isoforms. The mother and an unaffected sister were heterozygous for the mutation, which was not detected in 192 healthy Turkish controls or 1,200 controls of various other ancestries.
Degn et al. (2012) confirmed that the 9-year-old Turkish girl with 3MC syndrome and the W290X mutation lacked the MASP1, MASP3, and MAp44 isoforms encoded by the MASP1 gene. They found that the alternative complement pathway functioned normally in the patient and was unaffected by reconstitution of serum with MASP1 and MASP3. Conversely, the patient had a nonfunctional lectin pathway that could be restored by MASP1.
Dahl, M. R., Thiel, S., Matsushita, M., Fujita, T., Willis, A. C., Christensen, T., Vorup-Jensen, T., Jensenius, J. C. MASP-3 and its association with distinct complexes of the mannan-binding lectin complement activation pathway. Immunity 15: 127-135, 2001. [PubMed: 11485744] [Full Text: https://doi.org/10.1016/s1074-7613(01)00161-3]
Degn, S. E., Jensen, L., Hansen, A. G., Duman, D., Tekin, M., Jensenius, J. C., Thiel, S. Mannan-binding lectin-associated serine protease (MASP)-1 is crucial for lectin pathway activation in human serum, whereas neither MASP-1 nor MASP-3 is required for alternative pathway function. J. Immun. 189: 3957-3969, 2012. [PubMed: 22966085] [Full Text: https://doi.org/10.4049/jimmunol.1201736]
Dobo, J., Harmat, V., Beinrohr, L., Sebestyen, E., Zavodszky, P., Gal, P. MASP-1, a promiscuous complement protease: structure of its catalytic region reveals the basis of its broad specificity. J. Immun. 183: 1207-1214, 2009. [PubMed: 19564340] [Full Text: https://doi.org/10.4049/jimmunol.0901141]
Endo, Y., Sato, T., Matsushita, M., Fujita, T. Exon structure of the gene encoding the human mannose-binding protein-associated serine protease light chain: comparison with complement C1r and C1s genes. Int. Immun. 8: 1355-1358, 1996. [PubMed: 8921412] [Full Text: https://doi.org/10.1093/intimm/8.9.1355]
Leal, G. F., Baptista, E. V. P. Three additional cases of the Michels syndrome. Am. J. Med. Genet. 143A: 2747-2750, 2007. [PubMed: 17937425] [Full Text: https://doi.org/10.1002/ajmg.a.32029]
Leal, G. F., Silva, E. O., Duarte, A. R., Campos, J. F. Blepharophimosis, blepharoptosis, defects of the anterior chamber of the eye, caudal appendage, radioulnar synostosis, hearing loss and umbilical anomalies in sibs: 3MC syndrome? (Letter) Am. J. Med. Genet. 146A: 1059-1062, 2008. [PubMed: 18266249] [Full Text: https://doi.org/10.1002/ajmg.a.32252]
Matsushita, M., Thiel, S., Jensenius, J. C., Terai, I., Fujita, T. Proteolytic activities of two types of mannose-binding lectin-associated serine protease. J. Immun. 165: 2637-2642, 2000. [PubMed: 10946292] [Full Text: https://doi.org/10.4049/jimmunol.165.5.2637]
Rooryck, C., Diaz-Font, A., Osborn, D. P. S., Chabchoub, E., Hernandez-Hernandez, V., Shamseldin, H., Kenny, J., Waters, A., Jenkins, D., Al Kaissi, A., Leal, G. F., Dallapiccola, B., and 9 others. Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome. Nature Genet. 43: 197-203, 2011. [PubMed: 21258343] [Full Text: https://doi.org/10.1038/ng.757]
Sato, T., Endo, Y., Matsushita, M., Fujita, T. Molecular characterization of a novel serine protease involved in activation of the complement system by mannose-binding protein. Int. Immun. 6: 665-669, 1994. [PubMed: 8018603] [Full Text: https://doi.org/10.1093/intimm/6.4.665]
Sirmaci, A., Walsh, T., Akay, H., Spiliopoulos, M., Sakalar, Y. B., Hasanefendioglu-Bayrak, A., Duman, D., Farooq, A., King, M.-C., Tekin, M. MASP1 mutations in patients with facial, umbilical, coccygeal, and auditory findings of Carnevale, Malpuech, OSA, and Michels syndromes. Am. J. Hum. Genet. 87: 679-686, 2010. [PubMed: 21035106] [Full Text: https://doi.org/10.1016/j.ajhg.2010.09.018]
Takada, F., Seki, N., Matsuda, Y., Takayama, Y., Kawakami, M. Localization of the genes for the 100-kDa complement-activating components of Ra-reactive factor (CRARF and Crarf) to human 3q27-q28 and mouse 16B2-B3. Genomics 25: 757-759, 1995. [PubMed: 7759119] [Full Text: https://doi.org/10.1016/0888-7543(95)80027-j]
Takada, F., Takayama, Y., Hatsuse, H., Kawakami, M. A new member of the C1s family of complement proteins found in a bactericidal factor, Ra-reactive factor, in human serum. Biochem. Biophys. Res. Commun. 196: 1003-1009, 1993. [PubMed: 8240317] [Full Text: https://doi.org/10.1006/bbrc.1993.2349]
Takayama, Y., Takada, F., Nowatari, M., Kawakami, M., Matsu-ura, N. Gene structure of the P100 serine-protease component of the human Ra-reactive factor. Molec. Immun. 36: 505-514, 1999. [PubMed: 10475605] [Full Text: https://doi.org/10.1016/s0161-5890(99)00070-x]