The human ortholog of rhesus mannose-binding protein-A gene is an expressed pseudogene that localizes to Chromosome 10

Guo, Ning; Mogues, Tirsit; Weremowicz, Stanislawa; Morton, Cynthia C.; Sastry, Kedarnath N.

doi:10.1007/s003359900735

Cited by 73 publications

(50 citation statements)

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“…24 In mice, two different forms of MBL are encoded by two distinct functional genes known as mbl-a and mbl-c, which are positioned at different chromosomes, 14 and 19, respectively, 25 whereas the two human analogues MBL1PI and MBL2 are closely positioned on chromosome 10 (10q11.2-q21). 22,23 MBL-1 and MBL-2 have been detected in sera from the rhesus monkey, whereas in chimpanzee and in man MBL is only represented by MBL-2. 26 The protein-encoding region of MBL2 consists of four exons interrupted by three introns of 600, 1350 and 800 base pairs in size 21 (Figure 2).…”

Section: Historical Backgroundmentioning

confidence: 99%

“…21,22 However, an expressed MBL1 pseudogene has also been found (MBL1P1). 23 Ancient MBL1 and MBL2 are believed to have arisen by gene duplication from a common ancestral MBL gene. 24 In mice, two different forms of MBL are encoded by two distinct functional genes known as mbl-a and mbl-c, which are positioned at different chromosomes, 14 and 19, respectively, 25 whereas the two human analogues MBL1PI and MBL2 are closely positioned on chromosome 10 (10q11.2-q21).…”

Section: Historical Backgroundmentioning

confidence: 99%

“…48 Originally the human MBL1P1 pseudogene, which is an expressed pseudogene was described with an intron 1 splicing defect and two nonsense mutations (stop codons) positioned in exons 3 and 4. 23 However, it also possesses in codon 53 a glycine to arginine substitution. This substitution most likely disrupts the collagenous backbone structure of the protein because of its analogy with the human MBL2 codon 54 glycine to aspartic acid substitution.…”

Section: Maintenance Of High Frequencies Of Mbl2 Variant Alleles In Dmentioning

confidence: 99%

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Mannose-binding lectin and its genetic variants

et al. 2006

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Mannose-binding lectin (MBL) is a collagen-like serum protein that mediates activation of the complement system and is of importance for host defence. Common variant alleles situated both in the promoter and structural region of the human MBL gene (MBL2) influence the stability and the serum concentration of the protein. Epidemiological studies have suggested that genetically determined variation in MBL serum concentration influences the susceptibility to and the course of different types of infections, autoimmune, metabolic and cardiovascular diseases, but this is still a subject of debate. The fact that these genetic variations are very frequent indicates a dual role for MBL in host defence. In this survey, we summarize the current molecular understanding of human MBL genetics.

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Section: Historical Backgroundmentioning

confidence: 99%

Section: Historical Backgroundmentioning

confidence: 99%

Section: Maintenance Of High Frequencies Of Mbl2 Variant Alleles In Dmentioning

confidence: 99%

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Mannose-binding lectin and its genetic variants

et al. 2006

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“…22). Three different genetic polymorphisms in exon 1 of the human MBL2 gene (MBL1 is a pseudogene (23)) independently lead to reduced serum concentrations of MBL. Two interrupt the tandem repeat Gly-Xaa-Yaa in the first (Gly) position, and the third introduces a cysteine residue in the second position.…”

Section: Mannose-binding Lectin (Mbl)mentioning

confidence: 99%

Disease-associated Mutations in Human Mannose-binding Lectin Compromise Oligomerization and Activity of the Final Protein

Larsen

Madsen

Sim

et al. 2004

Journal of Biological Chemistry

205

199

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Deficiency of human mannose-binding lectin (MBL)caused by mutations in the coding part of the MBL2 gene is associated with increased risk and severity of infections and autoimmunity. To study the biological consequences of MBL mutations, we expressed wild type MBL and mutated MBL in Chinese hamster ovary cells. The normal MBL cDNA (WT MBL-A) was cloned, and the three known natural and two artificial variants were expressed in Chinese hamster ovary cells. When analyzed, WT MBL-A formed covalently linked higher oligomers with a molecular mass of about 300 -450 kDa, corresponding to 12-18 single chains or 4 -6 structural units. By contrast, all MBL variants formed a dominant band of about 50 kDa, with increasingly weaker bands at 75, 100, and 125 kDa corresponding to two, three, four, and five chains, respectively. In contrast to WT MBL-A, variant MBL formed noncovalent oligomers containing up to six chains (two structural units). MBL variants bound ligands with a markedly reduced capacity compared with WT MBL-A. Mutations in the collagenous region of human MBL compromise assembly of higher order oligomers, resulting in reduced ligand binding capacity and thus reduced capability to activate complement. Mannose-binding lectin (MBL)1 has been shown to be an important component of innate immunity and is a central recognition molecule of the lectin pathway of complement (for a recent review, see Ref. 1). MBL binds to an array of carbohydrate structures on surfaces of bacteria (2-4), yeast, viruses (5, 6), and parasitic protozoa (7,8). MBL functions as an opsonin (9), and the biological effect is mediated by direct killing via complement (10) through the lytic membrane attack complex or by promoting phagocytosis either by the MBL lectin pathway of complement or by direct binding to one or more cell surface receptors (11). The lectin pathway comprises at least three MBL-associated serine proteases (MASPs), namely MASP-1 (12), MASP-2 (13), and . Furthermore, the functional MBL-MASP complex contains a small MBL-associated protein (sMAP), also named MAp19, with no serine protease activity (15, 16). MASP-2 is a homologue of C1s of the classical complement pathway because it activates C4 and C2 (13). When MBL associated with MASP-2 binds to sugar groups on the surface of microbes, the MBL-MASP2 proenzyme is activated and cleaves sequentially C4 and C2, thereby creating the C4b2a complex, a potent C3 convertase. The MBL-MASP-1 complex is suggested to activate C3 directly (12). Whether both MASP-1 and MASP-2 are bound on the same MBL molecule is still unclear. Moreover, the biological role of sMAP, as well as the substrate for the recently discovered MASP-3, remains unclear at this moment (for a recent review on MASPs, see Ref. 17).MBL is a complex of six sets of homotrimers of a single polypeptide chain containing 228 amino acids (18 -21). This polypeptide consists of four domains ( Fig. 1): 1) a 20-amino acid N-terminal cysteine-rich domain involved in formation of intraand intersubunit disulfide bonds, 2) a collagen-like dom...

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“…105 Primers were designed for a continuous sequence of 10.0 kb including the MBL2 locus, 3.0 kb upstream from exon 1 and roughly 0.7 kb downstream of the poly-A tail (Appendix Table A1), and specifically excluded coamplification of the expressed but untranslated truncated pseudogene (MBL1P1) with three possible intraframe stop codons, which also resides on chromosome 10 (10q22.2-22.3, locus ID 8512). 106 The mVISTA web server was used to search for evolutionary conserved regions between human and mouse genomic sequences (http:// www-gsd.lbl.gov/vista) [107][108][109] derived from the homologue mouse mblc sequence (RefSeq NW_039687, NCBI build 32, October 2003, locus ID 17195).…”

Section: Detection Of Variant Sites By Re-sequencing Of Mbl2mentioning

confidence: 99%

Sequence analysis of the mannose-binding lectin (MBL2) gene reveals a high degree of heterozygosity with evidence of selection

et al. 2004

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Human mannose-binding protein (MBL) is a component of innate immunity. To capture the common genetic variants of MBL2, we resequenced a 10.0 kb region that includes MBL2 in 102 individuals representing four major US ethnic groups. In all, 87 polymorphic sites were observed, indicating a high level of heterozygosity (total p ¼ 18.3 Â 10 À4 ). Estimates of linkage disequilibrium across MBL2 indicate that it is divided into two blocks, with a probable recombination hot spot in the 3 0 end. Three non-synonymous SNPs in exon 1 of the encoding MBL2 gene and three upstream SNPs form common 'secretor haplotypes' that can predict circulating levels. Common variants have been associated with increased susceptibility to infection and autoimmune diseases. The high frequencies of B, C and D alleles in certain populations suggest a possible selective advantage for heterozygosity. There is limited diversity of haplotype structure; the 'secretor haplotypes' lie on a restricted number of extended haplotypes, which could include additional linked SNPs, which might also have possible functional implications. There is evidence for gene conversion in the region between the two blocks, in the last exon. Our data should form the basis for conducting MBL2 candidate gene association studies using a locus-wide approach. Keywords: mannose-binding lectin; innate immunity; genetic variation; recombination hot spot; gene conversion IntroductionThe human mannose-binding protein (MBL) is an important component of the innate immune system and provides first-line protection against pathogens as an 'ante-antibody'. 1 MBL is a C-type collectin that functions as a pattern-recognition molecule in the immediate response to invading organisms. Carbohydrate structures on the surfaces of microorganisms (bacteria, fungi and parasites) are recognized by MBL, 2-5 which, in turn, lead to opsonization or activation of the lectin pathway of complement via associated mannosebinding lectin serine proteases (MASP2). [6][7][8] Decreased serum levels of MBL have been correlated with an increased risk for infection in both healthy children and immunocompromised individuals. Circulating levels of MBL and functional activity are partially regulated by genetic variation in the MBL2 gene, which encodes MBL. 9,10 The MBL2 gene is located on chromosome 10q11.2-21 and consists of four exons. 11 Each of the three structural gene polymorphisms in exon 1, known as the B, C and D alleles, interfere with the formation of higher MBL oligomers, leading to alterations in function and circulating levels. [12][13][14][15] Two strongly linked single-nucleotide polymorphisms (SNPs) lie in the proximal promoter (known as L/H and X/Y), as well as an SNP in the 5 0 UTR (known as P/Q); together, these upstream SNPs are linked to the three independent nonsynonymous SNPs (ie, B, C and D) to form the 'secretor haplotypes', which have previously been shown to partially account for alterations in complement activation and decreased circulating levels of MBL. 7,9,10,[16][17][18][19][20] Using ...

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The human ortholog of rhesus mannose-binding protein-A gene is an expressed pseudogene that localizes to Chromosome 10

Cited by 73 publications

References 12 publications

Mannose-binding lectin and its genetic variants

Mannose-binding lectin and its genetic variants

Disease-associated Mutations in Human Mannose-binding Lectin Compromise Oligomerization and Activity of the Final Protein

Sequence analysis of the mannose-binding lectin (MBL2) gene reveals a high degree of heterozygosity with evidence of selection

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