Deficiency of mannan-binding lectin associated serine protease-2 due to missense polymorphisms

Thiel, Steffen; Steffensen, Rudi; Christensen, Ib Jarle; Ip, WK; Lau, YL; Reason, I. T. de Messias; Eiberg, Hans; Gadjeva, Mihaela; Ruseva, Marieta M.; Jensenius, Jens Christian

doi:10.1038/sj.gene.6364373

Cited by 90 publications

(131 citation statements)

References 42 publications

(60 reference statements)

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“…The MASP-2 levels in the 194 Zambian Africans were previously determined (11). When we divided the individuals in wt/wt and wt/R439H individuals, we found no significant difference in MASP-2 levels (Fig.…”

Section: Concentration and Activity Of Masp-2 In R439h Heterozygotesmentioning

confidence: 75%

“…We and others have described a number of amino acid exchange variants of MASP-2 (11,26). Of the reported variants, we decided not to produce rMASP-2 representing R118C because we have not found this allele in any of the populations that we have studied (11).…”

Section: Discussionmentioning

confidence: 99%

“…We and others have defined a number of nonsynonymous polymorphisms in the gene encoding MASP-2. We have previously identified and characterized the distribution of naturally occurring missense polymorphisms of MASP-2 in different ethnic populations, i.e., Caucasians, Hong Kong Chinese, Sub-Saharan Africans, South-African Indians, and Inuits, and have observed associations with circulating levels of MASP-2 (11). In the present study, we characterize the functional effects of the resulting naturally occurring variants of the MASP-2 protein through the production of the recombinant forms of the different MASP-2 allotypes.…”

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confidence: 99%

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Polymorphisms in Mannan-Binding Lectin (MBL)-Associated Serine Protease 2 Affect Stability, Binding to MBL, and Enzymatic Activity

Thiel

Kolev²,

Degn³

et al. 2009

The Journal of Immunology

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Mannan-binding lectin-associated serine protease 2 (MASP-2) is an enzyme of the innate immune system. MASP-2 forms complexes with the pattern recognition molecules mannan-binding lectin (MBL), H-ficolin, L-ficolin, or M-ficolin, and is activated when one of these proteins recognizes microorganisms and subsequently cleaves complement factors C4 and C2, thus initiating the activation of the complement system. Missense polymorphisms of MASP-2 exist in different ethnic populations. To further characterize the nature of these, we have produced and characterized rMASP-2s representing the following naturally occurring polymorphisms: R99Q, D120G, P126L, H155R, 156_159dupCHNH (CHNHdup), V377A, and R439H. Only very low levels of CHNHdup were secreted from the cells, whereas quantities similar to wild-type MASP-2 were found intracellularly, indicating that this mutation results in a misfolded protein. We found that D120G and CHNHdup could not associate with MBL, whereas R99Q, P126L, H155R, V377A, R439H, and wild-type MASP-2 bound equally well to MBL. Accordingly, when D120G and CHNHdup were mixed with MBL, no activation of complement factor C4 was observed, whereas R99Q, P126L, and V377A cleaved C4 with an activity comparable to wild-type MASP-2 and H155R slightly better. In contrast, the R439H variant was deficient in this process despite its normal binding to MBL. This variant was also not able to autoactivate in the presence of MBL and mannan. We find the R439H variant is common in Sub-Saharan Africans with a gene frequency of 10%. Our results indicate that individuals with different types of MASP-2 defects may be identified through genotyping.

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Section: Concentration and Activity Of Masp-2 In R439h Heterozygotesmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Polymorphisms in Mannan-Binding Lectin (MBL)-Associated Serine Protease 2 Affect Stability, Binding to MBL, and Enzymatic Activity

Thiel

Kolev²,

Degn³

et al. 2009

The Journal of Immunology

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“…This mutation renders MASP2 incapable of binding to MBL and therefore interrupts the MBL pathway of complement activation and also reduces the plasma concentration of MASP2 (48). Patients heterozygous for the MASP2 Asp 105Gly SNP have no impairment in the lectin complement pathway (10,11,51). Several additional variants have been identified in exon 3 of the MASP2 gene that do not cause a reduction of the levels or activity of the protein (31,52).…”

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confidence: 99%

Genotypes Coding for Low Serum Levels of Mannose-Binding Lectin Are Underrepresented among Individuals Suffering from Noninfectious Systemic Inflammatory Response Syndrome

Smithson

Perelló

Aibar

et al. 2010

Clin Vaccine Immunol

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Gene polymorphisms, giving rise to low serum levels of mannose-binding lectin (MBL) or MBL-associated protease 2 (MASP2), have been associated with an increased risk of infections. The objective of this study was to assess the outcome of intensive care unit (ICU) patients with systemic inflammatory response syndrome (SIRS) regarding the existence of functionally relevant MBL2 and MASP2 gene polymorphisms. The study included 243 ICU patients with SIRS admitted to our hospital, as well as 104 healthy control subjects. MBL2 and MASP2 single nucleotide polymorphisms were genotyped using a sequence-based typing technique. No differences were observed regarding the frequencies of low-MBL genotypes (O/O and XA/O) and MASP2 polymorphisms between patients with SIRS and healthy controls. Interestingly, ICU patients with a noninfectious SIRS had a lower frequency for low-MBL genotypes and a higher frequency for high-MBL genotypes (A/A and A/XA) than either ICU patients with an infectious SIRS or healthy controls. The existence of low-or / high-MBL genotypes or a MASP2 polymorphism had no impact on the mortality rates of the included patients. The presence of high-MBL-producing genotypes in patients with a noninfectious insult is a risk factor for SIRS and ICU admission.

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“…Likewise, MASP2 has been associated with immune response to several diseases, including Chagas disease (Boldt et al 2011), hepatitis C (Tulio et al 2011), and placental malaria (Holmberg et al 2012). Mutations in this gene (including rs12711521 (Boldt et al 2011), see Table S3) have been linked to both the activity (Thiel et al 2009) and expression levels (Thiel et al 2007) of the protein. Such a sharp signal at these loci may imply a differential disease landscape between the two populations.…”

Section: Application To Human Populationsmentioning

confidence: 99%

Learning Natural Selection from the Site Frequency Spectrum

Ronen

Udpa

Halperin

et al. 2013

Lecture Notes in Computer Science

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Genetic adaptation to external stimuli occurs through the combined action of mutation and selection. A central problem in genetics is to identify loci responsive to specific selective constraints. Many tests have been proposed to identify the genomic signatures of natural selection by quantifying the skew in the site frequency spectrum (SFS) under selection relative to neutrality. We build upon recent work that connects many of these tests under a common framework, by describing how selective sweeps affect the scaled SFS. We show that the specific skew depends on many attributes of the sweep, including the selection coefficient and the time under selection. Using supervised learning on extensive simulated data, we characterize the features of the scaled SFS that best separate different types of selective sweeps from neutrality. We develop a test, SFselect, that consistently outperforms many existing tests over a wide range of selective sweeps. We apply SFselect to polymorphism data from a laboratory evolution experiment of Drosophila melanogaster adapted to hypoxia and identify loci that strengthen the role of the Notch pathway in hypoxia tolerance, but were missed by previous approaches. We further apply our test to human data and identify regions that are in agreement with earlier studies, as well as many novel regions.N ATURAL selection works by preferentially favoring carriers of beneficial (fit) alleles. At the genetic level, the increased fitness may stem from two sources: either a de novo mutation that is beneficial in the current environment or new environmental stress leading to increased relative fitness of an existing allele. Over time, haplotypes carrying such variants start to dominate the population, causing reduced genetic diversity. This process, known as a selective sweep, is mitigated by recombination and can therefore be observed mostly in the vicinity of the beneficial allele. Improving our ability to detect the genomic signatures of selection is crucial for shedding light on genes responsible for adaptation to environmental stress, including disease.Many tests of neutrality have been proposed based on the site frequency spectrum (Tajima 1989;Fay and Wu 2000;Zeng et al. 2006;Chen et al. 2010;Udpa et al. 2011). We start by describing these tests in a common framework delineated by Achaz (2009). The data, namely genetic variants from a population sample, is typically represented as a matrix with m columns corresponding to segregating sites, and n rows corresponding to individual chromosomes. The sample is chosen from a much larger population of N diploid individuals, where chromosomes are connected by a (hidden) genealogy and mutations occurring in a certain lineage are inherited by all of its descendants ( Figure 1A). Thus, in the example shown in Figure 1A, the mutation at locus 4 appears in four chromosomes from the sample, or 0.5 frequency. Following Fu (1995), let j i denote the number of polymorphic sites at frequency i/n in a sample of size n. The site frequency spectrum (SFS) v...

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Deficiency of mannan-binding lectin associated serine protease-2 due to missense polymorphisms

Cited by 90 publications

References 42 publications

Polymorphisms in Mannan-Binding Lectin (MBL)-Associated Serine Protease 2 Affect Stability, Binding to MBL, and Enzymatic Activity

Polymorphisms in Mannan-Binding Lectin (MBL)-Associated Serine Protease 2 Affect Stability, Binding to MBL, and Enzymatic Activity

Genotypes Coding for Low Serum Levels of Mannose-Binding Lectin Are Underrepresented among Individuals Suffering from Noninfectious Systemic Inflammatory Response Syndrome

Learning Natural Selection from the Site Frequency Spectrum

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