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Norman Klopp

Publications and source records attributed to Norman Klopp.

30 records · Page 2Linked to original sources
PubMed2005

NOD1 variation, immunoglobulin E and asthma.

Asthma is a familial inflammatory disease of the airways of the lung. Microbial exposures in childhood protect against asthma through unknown mechanisms. The innate immune system is able to identify microbial components through a variety of pattern-recognition receptors (PRRs). NOD1 is an intracellular PRR that initiates inflammation in response to bacterial diaminopimelic acid (iE-DAP). The NOD1 gene is on chromosome 7p14, in a region that has been genetically linked to asthma. We carried out a systematic search for polymorphism in the gene. We found an insertion-deletion polymorphism (ND(1)+32656) near the beginning of intron IX that accounted for approximately 7% of the variation in IgE in two panels of families (P<0.0005 in each). Allele*2 (the insertion) was associated with high IgE levels. The same allele was strongly associated with asthma in an independent study of 600 asthmatic children and 1194 super-normal controls [odds ratio (OR) 6.3; 95% confidence interval (CI) 1.4-28.3, dominant model]. Differential binding of the two ND(1)+32656 alleles was observed to a protein from nuclei of the Calu 3 epithelial cell line. In an accompanying study, the deletion allele (ND(1)+32656*1) was found to be associated with inflammatory bowel disease. The results indicate that intracellular recognition of specific bacterial products affects the presence of childhood asthma.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Association of NOD1 polymorphisms with atopic eczema and related phenotypes.

BACKGROUND: Interactions with microbial pathogens are crucial for the maturation of the immune system. The nucleotide-binding oligomerization domain protein 1 (NOD1) is a cytosolic receptor sensing a muropeptide found mostly in gram-negative bacterial peptidoglycans. NOD1 is located on chromosome 7p14-p15, a region that has been linked with atopy. Recently, polymorphisms of the closely related NOD2 have been associated with atopy-related traits. OBJECTIVES: Within a large population-based cohort of German adults (n = 1417), a case-control population for atopic eczema (n = 454), and a large cohort of parent-offspring trios for atopic eczema (189 trios), we evaluated 11 NOD1 polymorphisms for associations with atopic phenotypes. Methods Subjects were phenotyped by standardized questionnaires and interviews, skin examination, and serum IgE measurements. Genotyping was performed by using matrix-assisted laser desorption ionization-time of flight mass spectrometry. RESULTS: Analyses revealed significant association of one NOD1 haplotype with atopic eczema in the population-based cohort ( P = .004) and the case-control population ( P = .003). Another NOD1 haplotype was associated with decreased total IgE ( P = .008). In addition, significant associations with total serum IgE levels were observed for polymorphisms rs2907748 ( P = .006), rs2907749 ( P = .012), and rs2075822 ( P = .018). These polymorphisms were significantly associated with atopic eczema and asthma in the family-based association analyses ( P = .001-.043). Seven polymorphisms showed significant transmission distortion for total IgE levels ( P values < .0001-.029). CONCLUSION: These data indicate that genetic variants within NOD1 are important determinants of atopy susceptibility.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Genotype-phenotype studies in bipolar disorder showing association between the DAOA/G30 locus and persecutory delusions: a first step toward a molecular genetic classification of psychiatric phenotypes.

OBJECTIVE: The authors previously reported an association between the D-amino acid oxidase activator (DAOA)/G30 locus and both schizophrenia and bipolar affective disorder. Given the presumed role of DAOA/G30 in the neurochemistry of psychosis and its localization in a schizophrenia and bipolar affective disorder linkage region (13q34), it was hypothesized that the bipolar affective disorder finding would be mainly due to an association with psychotic features. METHOD: The marker/haplotype associations obtained in a subset of 173 bipolar affective disorder patients with psychotic features were similar to those in the overall patient group, suggesting that stratification on the basis of psychotic features in general might be too crude a procedure. The authors therefore tested whether confining caseness to specific psychotic features would improve detection of genotype-phenotype correlations. RESULTS: In a logistic regression, "persecutory delusions" were found to be the only significant explanatory variable for the DAOA/G30 risk genotype among 21 OPCRIT symptoms of psychosis. The authors therefore tested for association between DAOA/G30 and bipolar affective disorder in the 90 cases with a history of persecutory delusions. Whereas this subset showed strong association (odds ratio=1.83 for the best marker), the remaining larger sample of 165 patients with no such history did not differ from comparison subjects, suggesting that the association between DAOA/G30 and bipolar affective disorder is due to persecutory delusions. This was confirmed in an independent study of 294 bipolar affective disorder patients and 311 comparison subjects from Poland, in which an association between bipolar affective disorder and DAOA/G30 was only seen when case definition was restricted to cases with persecutory delusions. CONCLUSIONS: These data suggest that bipolar affective disorder with persecutory delusions constitutes a distinct subgroup of bipolar affective disorder that overlaps with schizophrenia.

Adult↗
PubMed2004

Association of the interleukin-1 receptor antagonist gene with asthma.

The interleukin-1 cluster on human chromosome 2q12-2q14 harbors various promising candidate genes for asthma and other inflammatory diseases. We conducted a systematic association study with single-nucleotide polymorphisms (SNPs) located in candidate genes situated in this cluster. Single-marker, two-locus and three-locus haplotype analysis of SNPs yielded several significant results (p < 0.05-0.0021) for the human IL1RN gene encoding the IL-1 receptor antagonist protein, an antiinflammatory cytokine that plays an important role in maintaining the balance between inflammatory and antiinflammatory cytokines. These findings were replicated and confirmed in an independent Italian family sample in which significant, although weaker, association with asthma was detected. A sequencing approach to the coding region of the human IL1RN gene revealed additional DNA variants, from which a selection was also associated with the disease in German and Italian samples. Calculation of the linkage disequilibrium for the human IL1RN gene showed strong linkage disequilibrium for nearly all analyzed SNPs. Further haplotype analysis indicated that six SNPs are sufficient for tagging all haplotypes with a prevalence of more than 1%. The most frequent haplotype constructed from these SNPs was 1.4-fold overtransmitted in the German family sample.

Asthma↗
PubMed2004

A signal transducer and activator of transcription 6 haplotype influences the regulation of serum IgE levels.

BACKGROUND: Because of its central role in the IL-4/IL-13 pathway, the intracellular signaling molecule signal transducer and activator of transcription 6 ( STAT6 ) may be crucial for IgE production in asthma and allergy. OBJECTIVE: We analyzed the association between polymorphisms in the STAT6 gene and the regulation of serum IgE levels. Methods In a population of 1120 German schoolchildren (age 9-11 years), we genotyped 6 previously identified polymorphisms spanning the STAT6 gene by using the matrix-assisted laser desorption ionization-time of flight mass spectrometry method. Haplotypes were estimated and population-derived IgE percentiles (50% IgE > 60 IU/mL, 66% IgE > 115 IU/mL, and 90% IgE > 457 IU/mL) were modeled as outcome variables in haplotype-trend regression analysis. RESULTS: Polymorphisms located in intron 2 (C2892T) and the 3' untranslated region (T12888C) significantly and consistently contributed to elevated total serum IgE levels. One STAT6 haplotype showed increased odds ratios of 1.58 (95% CI, 1.08-2.32; P = .020), 1.82 (95% CI, 1.19-2.77; P = .006), and 3.92 (95% CI, 1.93-7.96; P = .0002) for elevated IgE levels at percentiles 50%, 66%, and 90%, respectively. Because C2892T is located within a nuclear factor kappaB transcription factor binding site, a functional role of this polymorphism is very likely. CONCLUSION: The data indicate that within the IL-4/IL-13 pathway, genetic variants in the STAT6 gene significantly contribute to the regulation of serum IgE levels.

Base Sequence↗
PubMed2004

Genetic and allelic heterogeneity of Cryg mutations in eight distinct forms of dominant cataract in the mouse.

PURPOSE: The purpose of this study was the characterization of eight new dominant cataract mutations. METHODS: Lenses of mutant mice were described morphologically and histologically. Each mutation was mapped by linkage studies. The candidate genes (the Cryg gene cluster and the closely linked Cryba2 gene) were sequenced. RESULTS: Molecular analysis confirmed all mutations in Cryg genes. Five mutations lead to amino acid exchanges, two are due to premature stop codons, and one is a 10-bp deletion in the Cryge gene. Morphologically, mutant carriers expressed nonsyndromic cataracts, ranging from diffuse lenticular opacities (Crygd(ENU910) and Cryge(ENU449)), to dense nuclear and subcortical opacity (Crygd(K10), Crygc(MNU8), Cryge(Z2), Crygd(ENU4011), and Cryge(ADD15306)), to dense nuclear opacity and ruptured lenses (Cryga(ENU469)). Results of histologic analyses correlate well with the severity of lens opacity, ranging from alterations in the process of secondary fiber nucleus degradation to lens vacuoles, fiber degeneration, and disruption of the lens capsule. CONCLUSIONS: In total, 20 mutations have been described that affect the Cryg gene cluster: Nine mutations affect the Cryge gene, but only one affects the Crygb or Crygf genes. No mutation was observed in the closely linked Cryba2. Two mutations occur at the same site in the Crygd and Cryge genes (Leu45-->Pro). The unequal distribution of mutations suggests hot spots in the Cryg genes. The overall high number of mutations in these genes demonstrates their central role in the maintenance of lens transparency.

Alleles↗
PubMed2002

Altered aggregation properties of mutant gamma-crystallins cause inherited cataract.

Protein inclusions are associated with a diverse group of human diseases ranging from localized neurological disorders through to systemic non-neuropathic diseases. Here, we present evidence that the formation of intranuclear inclusions is a key event in cataract formation involving altered gamma-crystallins that are un likely to adopt their native fold. In three different inherited murine cataracts involving this type of gamma-crystallin mutation, large inclusions containing the altered gamma-crystallins were found in the nuclei of the primary lens fibre cells. Their formation preceded not only the first gross morphological changes in the lens, but also the first signs of cataract. The inclusions contained filamentous material that could be stained with the amyloid-detecting dye, Congo red. In vitro, recombinant mutant gammaB-crystallin readily formed amyloid fibrils under physiological buffer conditions, unlike wild-type protein. These data suggest that this type of cataract is caused by a mechanism involving the nuclear targeting and deposition of amyloid-like inclusions. The mutant gamma-crystallins initially disrupt nuclear function, but then this progresses to a full cataract phenotype.

Amyloid↗
PubMed2002

STAT6 as an asthma candidate gene: polymorphism-screening, association and haplotype analysis in a Caucasian sib-pair study.

The human signal transducer and activator of transcription 6 (STAT6) gene represents one of the most promising candidate genes for asthma and other inflammatory diseases on the chromosomal region 12q13-q24. Therefore we screened all 23 exons, including parts of the neighbouring introns, as well as the promoter region for common polymorphisms and tested them for linkage/association with asthma and related traits (total serum IgE level, eosinophil cell count and SLOPE of the dose-response curve after bronchial challenge) in a Caucasian sib-pair study (108 families with at least two affected children). We could identify 13 single nucleotide polymorphisms (SNPs), which are all non-coding. A recently described dinucleotide (GT) repeat in exon 1 was also examined. Besides the confirmation of the four alleles described elsewhere we could identify a new one, named allele A5. Neither the SNPs nor the GT repeat showed linkage/association to asthma. Two intronic SNPs and one SNP in the 3'untranslated region of the gene showed weak association to total IgE levels (P = 0.0200, 0.0260 and 0.0280, respectively), whereas a significant association was found between a SNP in intron 18 and an increase in total IgE levels (P = 0.0070). However, the most promising effect was seen between allele A4 of the GT repeat polymorphism and an increase in eosinophil cell count (P = 0.0010). From these findings we conclude that the human STAT6 gene is rather involved in the development of eosinophilia and changes in total IgE levels than contributing to the pathogenesis of asthma.

Adult↗
PubMed2002

Ethylnitrosourea-induced base pair substitution affects splicing of the mouse gammaE-crystallin encoding gene leading to the expression of a hybrid protein and to a cataract.

A novel ENU-induced mutation in the mouse leading to a nuclear and cortical opacity of the eye lens (ENU418) was mapped to proximal chromosome 1 by a genome-wide mapping approach. It suggests that the cluster of gamma-crystallin encoding genes (Cryg) and the betaA2-crystallin encoding gene Cryba2 are excellent candidate genes. An A --> G exchange in the middle of intron 1 of the Cryge gene was found as the only alteration cosegregating with the cataractous phenotype. The mutation was confirmed by the presence of a novel restriction site for ApaI in the corresponding genomic DNA fragment. The mutation represses splicing of intron 1; the additional 92 bp in the corresponding cDNA leads to a frameshift and the expression of a novel hybrid protein containing 3 amino acids of the gammaE-crystallin at the N terminus, but 153 novel amino acids. The Cryge(ENU418) protein has a calculated molecular mass of approximately 15.6 kD and an alkaline isoelectric point (pH 10.1) and is predicted to have two hydrophobic domains. Western blot analysis using a polyclonal antibody against the hydrophilic C-terminal part of the Cryge(ENU418)-specific protein demonstrated its stable expression in the cataractous lenses; it was not found in the wild types. Histological analysis of the cataractous lenses indicated that the expression of the new protein disrupts the cellular structure of the eye lens.

Alkylating Agents↗
PubMed2002

Crygf(Rop): the first mutation in the Crygf gene causing a unique radial lens opacity.

PURPOSE: The Rop (radial opacity) mutation, which was recovered in a mutagenicity screen after paternal treatment with procarbazine, was analyzed to determine phenotype, chromosomal localization, candidate genes, and molecular lesion. METHODS: Native lenses were photographed under a dissecting microscope. Histologic sections of the eye were made according to standard procedures. Fine mapping of the mutation in relation to microsatellite markers for mouse chromosome 1 was performed. Candidate genes were amplified by PCR from cDNA or genomic DNA and sequenced. RESULTS: The nuclear opacity of the heterozygous mutants showed radial structures, whereas the opacity of the homozygotes was homogenous. The histologic analysis revealed changes in the lens nucleus, which corresponds to the pronounced opacification in lenses of homozygous mutants. The allelism of Rop to the Cat2 group of dominant cataracts on mouse chromosome 1 was confirmed by linkage to microsatellite markers D1Mit156 and D1Mit181. The cluster of the Cryg genes and the closely linked Cryba2 gene were tested as candidates. A T-->A exchange in exon 2 of the Crygf gene leads to a Val-->Glu exchange in codon 38 and was considered to be causative for the cataract phenotype; therefore, Crygf(Rop) has been suggested as the designation for the mutation. CONCLUSIONS: Crygf(Rop) is the first mutation affecting the Crygf gene. Dominant cataract mutations for all six Cryg genes on mouse chromosome 1 have now been characterized, demonstrating the importance of this gene cluster in lens transparency.

Animals↗
PubMedDate not supplied

Further genetic heterogeneity for autosomal dominant human sutural cataracts.

A unique sutural cataract was observed in a 4-generation German family to be transmitted as an isolated autosomal, dominant trait. Since mutations in the gamma-crystallin encoding CRYG genes have previously been demonstrated to be the most frequent reason for isolated congenital cataracts, all 4 active CRYG genes have been sequenced. A single base-pair change in the CRYGA gene has been shown, leading to a premature stop codon. This was not observed in 170 control individuals. However, it did not segregate with the disease phenotype. This is the first truncating mutation in an active CRYG gene without a dominant phenotype. As the CRYGA mutation did not explain the cataract, several other candidate loci (CCV, GJA8, CRYBB2, BFSP2, MIP, GJA8, CENTRAL POUCH-LIKE, CRYBA1) were investigated by microsatellite markers and linkage analysis, but they were excluded based on the combination of haplotype analysis and two-point linkage analysis. The phenotype in this family is due to a mutation in another sutural cataract gene yet to be identified.

Amino Acid Sequence↗