Molecular basis of opsonic defect in immunodeficient children

Sumiya, M.; Tabona, P; Arai, T.; Summerfield, John A.; Super, Michael; Levinsky, Roland J.; Turner, M. W.

doi:10.1016/0140-6736(91)93263-9

Cited by 506 publications

(367 citation statements)

References 7 publications

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“…12 Sequencing the exons of the MBL2 gene from three children who had low MBL serum concentrations and phagocytic deficiency and were suffering from recurrent infections revealed that each child carried a point mutation at codon 54 in exon 1 that caused a substitution of glycine with aspartic acid (GGC to GAC) (allele B, the normal allele is given the name A) (Figure 4). 37 Investigation of family members of the probands suggested an autosomal dominant inheritance of low MBL concentration because the median protein concentration decreased about 10 times in individuals with the heterozygous genotype. It was suggested that the decreasing effect of the B allele on the MBL serum concentration was due to the incorrect assembly of the MBL triple helix structure.…”

Section: Historical Backgroundmentioning

confidence: 99%

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%

Mannose-binding lectin and its genetic variants

et al. 2006

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“…In 1989, Super et al discovered that many children with recurrent infections were MBL-deficient. Subsequently, MBL deficiency due to MBL-2 gene exon 1 mutations (B, C, and D variants) and three other SNPs in promoter region (H/L, Y/X, and P/Q) were observed in children with a syndrome of frequent infections and opsonin deficiency (Sumiya et al, 1991;Summerfield et al, 1997, Turner andHamvas, 2000). Since the first description by Turner's group (Super et al 1989), MBL deficiency has been found in association with different autoimmune (e.g.…”

Section: Components Of the Lectin Pathwaymentioning

confidence: 99%

Complement genetics, deficiencies, and disease associations

Mayilyan

2012

Protein Cell

148

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The complement system is a key component of innate immunity. More than 45 genes encoding the proteins of complement components or their isotypes and subunits, receptors, and regulators have been discovered. These genes are distributed throughout different chromosomes, with 19 genes comprising three significant complement gene clusters in the human genome. Genetic deficiency of any early component of the classical pathway (C1q, C1r/s, C2, C4, and C3) is associated with autoimmune diseases due to the failure of clearance of immune complexes (IC) and apoptotic materials, and the impairment of normal humoral response. Deficiencies of mannan-binding lectin (MBL) and the early components of the alternative (factor D, properdin) and terminal pathways (from C3 onward components: C5, C6, C7, C8, C9) increase susceptibility to infections and their recurrence. While the association of MBL deficiency with a number of autoimmune and infectious disorders has been well established, the effects of the deficiency of other lectin pathway components (ficolins, MASPs) have been less extensively investigated due to our incomplete knowledge of the genetic background of such deficiencies and the functional activity of those components. For complement regulators and receptors, the consequences of their genetic deficiency vary depending on their specific involvement in the regulatory or signalling steps within the complement cascade and beyond. This article reviews current knowledge and concepts about the genetic load of complement component deficiencies and their association with diseases. An integrative presentation of genetic data with the latest updates provides a background to further investigations of the disease association investigations of the complement system from the perspective of systems biology and systems genetics.

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“…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 the six SNPs above, it is possible to map circulating levels against the seven common 'secretor haplotypes' in at least 85% of subjects.…”

Section: Introductionmentioning

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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Molecular basis of opsonic defect in immunodeficient children

Cited by 506 publications

References 7 publications

Mannose-binding lectin and its genetic variants

Mannose-binding lectin and its genetic variants

Complement genetics, deficiencies, and disease associations

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

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