A new frequent allele is the missing link in the structural polymorphism of the human mannan-binding protein

Madsen, Hans O.; Garred, Peter; Kurtzhals, Jørgen A. L.; Lamm, L. U.; Ryder, Lars P.; Thiel, Steffen; Svejgaard, A.

doi:10.1007/bf00163962

Cited by 457 publications

(379 citation statements)

References 21 publications

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“…Subsequently, a third MBL substitution was found in codon 52 (CGT to TGT) causing an arginine to be substituted with a cysteine (allele D) (Figure 4). 41 This allele had a frequency of 0.05 in both East Africans and Caucasians, but as for the C allele it was virtually absent in Asians and in Inuits and even in West Africans. The D allele also had a decreasing effect on the median MBL concentration in A/D heterozygotes, but the effect was less dramatic and the range in serum concentration was wider compared to the other two alleles.…”

Section: Historical Backgroundmentioning

confidence: 96%

“…However, the LYA haplotype could be further subdivided into additional haplotypes when a polymorphism (P/Q) located in the 5 0 -untranslated portion of exon 1 (position þ 4) is taken into consideration. 41,43 Thus, the MBL LY type consists of the following haplotypes: LYPA, LYPB, LYQA and LYQC. A difference in the serum concentration between the LYPA and LYQA haplotypes can also be observed showing that each of the identified promoter haplotypes is associated with different MBL serum levels.…”

Section: Historical Backgroundmentioning

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: 96%

Section: Historical Backgroundmentioning

confidence: 99%

Mannose-binding lectin and its genetic variants

et al. 2006

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“…A deficiency in MBL can cause a vulnerability to infection [4][5][6]. It is well known that there are three point mutations in codons 52, 54 and 57 in exon 1 of the human MBL structural gene encoding collagen-like sequences [7][8][9]. These mutations are thought to interfere with the maintenance of a stable quarternary structure and to promote degradation in the circulation [10][11][12] or to impair secretion [11,13], leading to the MBL deficiency.…”

Section: Introductionmentioning

confidence: 99%

Relationship between gene polymorphisms of mannose‐binding lectin (MBL) and two molecular forms of MBL

et al. 2003

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Mannose-binding lectin (MBL) activates complement through MBL-associated serine proteases (MASP). A deficiency in MBL due to mutations at exon 1 of the human MBL gene is reported to cause vulnerability to infection. We examined sera of known MBL genotype by gel filtration and assessed their elution patterns using an ELISA for MBL and identified two MBL forms, a high-molecular-mass form and a lower-molecular-mass form. By the identification of either or both forms in individual sera, three types of patterns emerged: type 1 consisted of a high-molecular form; type 2, of a low-molecular form; and type 3, of both forms. Types 1, 2 and 3 corresponded, respectively, to a wild type (A/A), a homozygous mutation at codon 54 (B/B) and their heterozygote (A/B). One exception was a heterozygous LXPA/LYPB phenotype that exhibited the type-2 pattern. Binding to mannan and MASP-1/3 occurred exclusively with the high-molecular form. An apparent MBL deficiency does not in fact represent a deficiency in MBL molecules but rather the presence of circulating oligomeric mutant MBL with impaired function.

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“…[29][30][31] Plasma levels and functional activity of the collectins are known to be determined by polymorphisms in exon 1 and in the promotor region of the MBL2 gene, and thus a genetic susceptibility to the development of severe infections has been suggested as genetic variants associated with low MBL concentrations revealed a clinical phenotype. 3,[7][8][9][10] Preterm infants, known to exhibit a markedly increased risk for the development of severe infections, may critically depend on their innate immune response, as the presence of early-onset and nosocomial infections mainly determines acute and long-term morbidity and mortality in this population, especially regarding the development of neurological and pulmonary impairment. [17][18][19] Especially, the development of chronic lung disease in preterm infants is known to be triggered by infectious complications and ongoing inflammatory processes.…”

Section: Discussionmentioning

confidence: 99%

“…7 Numerous disease association studies suggested an important role for MBL in relation to the acquisition or the clinical course of infectious diseases in children and adults. 3,[7][8][9][10] Especially in immunocompromised individuals, MBL deficiency appears to exert effects on susceptibility and severity of infectious diseases. [11][12][13][14][15][16] Because their adaptive immunity has not yet been developed, MBL is particularly important in neonates in whom immune defense depends on maternal antibodies and innate defense mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Association of polymorphisms in the mannose-binding lectin gene and pulmonary morbidity in preterm infants

et al. 2007

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Deficiency in the collectin mannose-binding lectin (MBL) increases the risk for pulmonary and systemic infections and its complications in children and adults. The aim of this prospective cohort study was to determine the genetic association of sequence variations within the MBL gene with systemic infections and pulmonary short-and long-term complications in preterm infants below 32 weeks gestational age (GA). Three single-nucleotide polymorphisms (SNPs) in the coding region and one SNP in the promotor region of MBL2 were genotyped by direct sequencing and with sequence-specific probes in 284 newborn infants o32 weeks GA. Clinical variables were comprehensively monitored. An association was found between two SNPs and the development of bronchopulmonary dysplasia (BPD), defined as persistent oxygen requirement at 36 weeks postmenstrual age, adjusting for covariates GA, grade of respiratory distress syndrome and days on mechanical ventilation (rs1800450 (exon 1 at codon 54, B variant): odds ratio dominant model (OR) ¼ 3.59, 95% confidence interval (CI) ¼ 1.62-7.98; rs7096206 (À221, X variant): OR ¼ 2.40, 95% CI ¼ 1. 16-4.96). Haplotype analyses confirmed the association to BPD, and a single haplotype (frequency 56%) including all SNPs in their wild-type form showed a negative association with the development of BPD. We detected no association between the MBL gene variations and the development of early-onset infections or further pulmonary complications. Frequent variants of the MBL gene, leading to low MBL concentrations, are associated with the diagnosis of BPD in preterm infants. This provides a basis for potential therapeutic options and further genetic and proteomic analysis of the function of MBL in the resistance against pulmonary long-term complications in preterm infants.

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A new frequent allele is the missing link in the structural polymorphism of the human mannan-binding protein

Cited by 457 publications

References 21 publications

Mannose-binding lectin and its genetic variants

Mannose-binding lectin and its genetic variants

Relationship between gene polymorphisms of mannose‐binding lectin (MBL) and two molecular forms of MBL

Association of polymorphisms in the mannose-binding lectin gene and pulmonary morbidity in preterm infants

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