Detection of structural gene mutations and promoter polymorphisms in the mannan-binding lectin (MBL) gene by polymerase chain reaction with sequence-specific primers

Steffensen, Rudi; Thiel, Steffen; Varming, Kim; Jersild, Casper; Jensenius, Jens Christian

doi:10.1016/s0022-1759(00)00198-8

Cited by 321 publications

(381 citation statements)

References 22 publications

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“…The frequencies of the different mutations were similar and were in HardyWeinberg equilibrium in the subjects recruited at both institutions (Hospital of Girona and Hospital of Málaga), and these results were therefore pooled for further analysis. The frequencies of the MBL B, C and D mutations were 23.4, 3.7 and 9.2% respectively, similar to those found in other Caucasian populations [12][13][14]. The serum concentration of MBL protein was markedly different among these groups: the median value was 2,589±μg/ml (95% CI: 2,334-2,844 μg/ml) in wild-type (A allele); 771.8 μg/ml (95% CI: 602.4-941.2) in subjects heterozygous for only one mutation (any of the three of exon 1); 144.9 μg/ml (95% CI: 17.5-272.3) in subjects homozygous for one mutation; and 25 μg/ml (95% CI: 10.9-39.2) in subjects who were compound heterozygotes (heterozygous for at least two different mutations) (p<0.00001).…”

Section: Mbl2 Gene Variants In Association With Obesitysupporting

confidence: 86%

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Protection from inflammatory disease in insulin resistance: the role of mannan-binding lectin

Fernández-Real¹,

Strączkowski

Vendrell

et al. 2006

Diabetologia

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Aims/hypothesis Decreased sensing of the innate immune system may lead to chronic activation of the inflammatory cascade. We hypothesised that mannan-binding lectin (MBL) deficiency may confer risk of obesity and insulin resistance. Materials and methods We performed a cross-sectional study of MBL protein concentration (n=434) and MBL2 gene mutations (exon 1) (n=759) in association with obesity, markers of inflammation and insulin action (euglycaemic clamp, n=113), and a longitudinal study of MBL protein before and after weight loss in obese patients (n=10). We also studied the effects of MBL in vitro in muscle cells and circulating MBL-A (mouse equivalent of human MBL) in a mouse model. Results Among 434 consecutive non-diabetic men, the ageadjusted serum MBL concentration was lower in obese subjects than in lean subjects (median: 959 μg/ml [interquartile range: 116.8-2,044 μg/ml] vs 1,365 [467-2,513] μg/ml; p=0.01) and was accompanied by increased serum inflammatory markers. Insulin action correlated significantly with serum MBL (r=0.49, p<0.0001). Serum MBL concentration increased by a median of 110.2% after weight loss. The change in serum concentration of MBL was positively associated with the increase in insulin sensitivity (r=0.713, p=0.021). At least one MBL2 gene mutation was present in 48.2% of obese vs 39.3% of non-obese subjects (p=0.037). The plasma concentration of MBL-A was lower in insulinresistant obese ob/ob mice, as was the glucose/insulin ratio. Incubation of rat soleus muscle with human MBL markedly increased fatty acid oxidation. Conclusions/interpretation These findings suggest that MBL, previously thought only to be involved in inflammation and immune system function, affects metabolic pathways.

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Section: Mbl2 Gene Variants In Association With Obesitysupporting

confidence: 86%

“…The normal allele of MBL2 is named A and the common designation for the variant alleles is O. Each of the three variant alleles influences the stability of the final protein product, resulting in reduced serum levels and a dysfunctional MBL variant with a lower molecular weight than the normal protein [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Protection from inflammatory disease in insulin resistance: the role of mannan-binding lectin

Fernández-Real¹,

Strączkowski

Vendrell

et al. 2006

Diabetologia

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“…The median level of MBL in serum is 800-1,000 μg/l, but in one-third of the population the level is <500 μg/l and in about one-tenth even lower than 100 μg/l [17,18].…”

Section: Discussionmentioning

confidence: 96%

Mannose-binding lectin deficiency attenuates renal changes in a streptozotocin-induced model of type 1 diabetes in mice

et al. 2007

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Aims/hypothesis An increasing amount of evidence indicates that mannose-binding lectin (MBL) plays a role in the development of diabetic nephropathy. The main objective of the study was to analyse whether MBL influences the effects of diabetes on the kidneys. Materials and methods In one group of wild-type mice and in one group of MBL double knockout mice we induced diabetes by the use of streptozotocin as a model of type 1 diabetes. Two groups of non-diabetic mice, wild-type and MBL knockout, were also included. By two-way ANOVA we evaluated if MBL modulated the effects of diabetes by testing the interaction between diabetes and MBL. Results MBL interacted with the effects of diabetes on three outcome measures: kidney weight (p<0.001), urinary albumin excretion (p=0.001) and the expression of collagen IVα1 (Col4a1) mRNA (p=0.002). This means that the effects that diabetes normally has on these parameters were significantly modified by MBL. MBL showed a tendency to interact with the effects of diabetes on glomerular basement membrane thickness and total mesangial volume (p=0.065 and p=0.063, respectively). Glomerular volume and total mesangial volume were significantly smaller in animals lacking MBL than in wild-type animals (p=0.006 and p=0.047, respectively). Conclusions/interpretation These findings, for the first time, show that the degree of kidney alteration as a consequence of diabetes is modified by MBL. These findings support a pivotal role of MBL in the development of diabetic kidney disease.

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“…12,13 In African, European, Asian and native American populations, the promoter haplotypes HYP and LYQ cause the highest and LXP the lowest MBL concentration in plasma [13][14][15][16][17][18][19] (see Table 1 for the official nomenclature of these and other MBL2 variants). Lower polymerization level and reduced plasma concentration of MBL multimers are associated with the variants B, C and D, which occur in the first exon of the gene.…”

Section: Introductionmentioning

confidence: 99%

Association of a new mannose-binding lectin variant with severe malaria in Gabonese children

et al. 2006

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Mannose-binding lectin (MBL2) variants that decrease the plasma level of the protein or encode dysfunctional proteins are frequently associated with the severity of a number of infections and autoimmune disorders. The high frequencies of these variants in most populations of the world are probably maintained by some selective advantage against widespread diseases. We found 14 new MBL2 allelic haplotypes, two of them with non-synonymous variants, by screening 136 children with uncomplicated malaria, 131 children with severe malaria and 39 older healthy schoolchildren. We also found a significant association of a novel variant with susceptibility to severe malaria (P ¼ 0.010). Increased MBL plasma levels and corresponding MBL2 genotypes were associated with lower concentration of several cytokines and chemokines in plasma of malaria patients. We suggest that malaria could have been one of the evolutionary driving forces shaping the MBL2 polymorphism in the African population.

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Detection of structural gene mutations and promoter polymorphisms in the mannan-binding lectin (MBL) gene by polymerase chain reaction with sequence-specific primers

Cited by 321 publications

References 22 publications

Protection from inflammatory disease in insulin resistance: the role of mannan-binding lectin

Protection from inflammatory disease in insulin resistance: the role of mannan-binding lectin

Mannose-binding lectin deficiency attenuates renal changes in a streptozotocin-induced model of type 1 diabetes in mice

Association of a new mannose-binding lectin variant with severe malaria in Gabonese children

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