CNTNAP2 variants affect early language development in the general population

Early language development is known to be under genetic influence, but the genes affecting normal variation in the general population remain largely elusive. Recent studies of disorder reported that variants of the CNTNAP2 gene are associated both with language deficits in specific language impairment (SLI) and with language delays in autism. We tested the hypothesis that these CNTNAP2 variants affect communicative behavior, measured at 2 years of age in a large epidemiological sample, the Western Australian Pregnancy Cohort (Raine) Study. Singlepoint analyses of 1149 children (606 males and 543 females) revealed patterns of association which were strikingly reminiscent of those observed in previous investigations of impaired language, centered on the same genetic markers and with a consistent direction of effect (rs2710102, P = 0.0239; rs759178, P = 0.0248). On the basis of these findings, we performed analyses of four-marker haplotypes of rs2710102-rs759178-rs17236239-rs2538976 and identified significant association (haplotype TTAA, P = 0.049; haplotype CGAG, [corrected] P = .0014). Our study suggests that common variants in the exon 13-15 region of CNTNAP2 influence early language acquisition, as assessed at age 2, in the general population. We propose that these CNTNAP2 variants increase susceptibility to SLI or autism when they occur together with other risk factors.     

Allelic variants of human calcitonin receptor in the Japanese population

Evidence from cDNA cloning has shown that calcitonin receptors (CTRs) have seven potential transmembrane domains. In this study, structural analysis of CTRs from ten cultured human tumor cell lines and 117 human blood samples demonstrated allelic variants at the 1377th nucleotide in intracellular domain 4, expressing either proline or leucine as the 463rd amino acid. It was found that the variant with proline at this site was the more prevalent type of CTR among the Japanese population. Received: 21 June 1996     

Prevalence of rare F5 variants in general population from Bosnia and Herzegovina

Molecular Biology Reports - Human gene F5, encoding coagulation factor V, was previously reported to be highly polymorphic. Apart from FV Leiden, several other rare variants have been detected in...     

Functional characterization of Ape1 variants identified in the human population

Apurinic/apyrimidinic (AP) sites are common mutagenic and cytotoxic DNA lesions. Ape1 is the major human repair enzyme for abasic sites and incises the phosphodiester backbone 5′ to the lesion to initiate a cascade of events aimed at removing the AP moiety and maintaining genetic integrity. Through resequencing of genomic DNA from 128 unrelated individuals, and searching published reports and sequence databases, seven amino acid substitution variants were identified in the repair domain of human Ape1. Functional characterization revealed that three of the variants, L104R, E126D and R237A, exhibited ~40–60% reductions in specific incision activity. A fourth variant, D283G, is similar to the previously characterized mutant D283A found to exhibit ~10% repair capacity. The most common substitution (D148E; observed at an allele frequency of 0.38) had no impact on endonuclease and DNA binding activities, nor did a G306A substitution. A G241R variant showed slightly enhanced endonuclease activity relative to wild-type. In total, four of seven substitutions in the repair domain of Ape1 imparted reduced function. These reduced function variants may represent low penetrance human polymorphisms that associate with increased disease susceptibility.     

Functional capacity of XRCC1 protein variants identified in DNA repair-deficient Chinese hamster ovary cell lines and the human population

XRCC1 operates as a scaffold protein in base excision repair, a pathway that copes with base and sugar damage in DNA. Studies using recombinant XRCC1 proteins revealed that: a C389Y substitution, responsible for the repair defects of the EM-C11 CHO cell line, caused protein instability; a V86R mutation abolished the interaction with POLβ, but did not disrupt the interactions with PARP-1, LIG3α and PCNA; and an E98K substitution, identified in EM-C12, reduced protein integrity, marginally destabilized the POLβ interaction, and slightly enhanced DNA binding. Two rare (P161L and Y576S) and two frequent (R194W and R399Q) amino acid population variants had little or no effect on XRCC1 protein stability or the interactions with POLβ, PARP-1, LIG3α, PCNA or DNA. One common population variant (R280H) had no pronounced effect on the interactions with POLβ, PARP-1, LIG3α and PCNA, but did reduce DNA-binding ability. When expressed in HeLa cells, the XRCC1 variants—excluding E98K, which was largely nucleolar, and C389Y, which exhibited reduced expression—exhibited normal nuclear distribution. Most of the protein variants, including the V86R POLβ-interaction mutant, displayed normal relocalization kinetics to/from sites of laser-induced DNA damage: except for E98K and C389Y, and the polymorphic variant R280H, which exhibited a slightly shorter retention time at DNA breaks.     

WNT10A variants are associated with non-syndromic tooth agenesis in the general population

Tooth agenesis is the most common developmental dental anomaly. Absence of one or two permanent teeth is found in the majority of affected subjects. Very few patients suffer severe tooth agenesis. Recent studies revealed that WNT10A gene mutations caused syndromic and isolated severe tooth agenesis. In this study, to determine the contribution of WNT10A variants in different severities of tooth agenesis, we investigated the association between WNT10A variants and non-syndromic tooth agenesis in a Chinese population consisting of 505 tooth agenesis patients and 451 normal controls. Twenty-three novel non-synonymous variants were identified. WNT10A variants were detected in 15.8 % (75/474) of patients with 1–3 missing teeth and 51.6 % (16/31) of patients with 4 or more missing teeth. As compared with a frequency of 3.1 % in individuals with full dentition, variant allele frequencies were significantly elevated in both groups with tooth agenesis (p values of 1.00 × 10^?6 and 3.89 × 10^?23, respectively). Our findings showed that WNT10A variants were associated with non-syndromic tooth agenesis from mild to severe tooth agenesis, and the more severe tooth agenesis, the stronger association. Biallelic genotypes of WNT10A variants may have a pathogenic effect on tooth development. Presence of a single variant allele would be predisposing for causation with low penetrance. Together with WNT10A variant, there should be other genetic or environmental factors leading to biallelic variant-related variable clinical manifestations and single allele variant-related low penetrance. The frequent missing tooth positions in the WNT10A-related cases were consistent with that in the general population, suggesting WNT10A plays a critically important role in the etiology of general tooth agenesis.     

Investigation of relationship between IL-6 gene variants and hypertension in Turkish population

Hypertension (HT) is a common and life threating health problem worldwide leading to stroke, heart attack and renal failure. It is characterized by elevated blood pressure forced heart load. Human interleukin-6 (IL-6) and C- reactive protein (CRP) are known to be involved in inflammatory processes. IL-6 gene is a polymorphic gene which −174 G/C is a common and −572 G/C is a rare polymorphisms identified in promoter region. Publications on IL-6 gene polymorphisms raised the question whether this gene polymorphisms lead to susceptibility to HT or not. To investigate the effects of IL-6 gene −174 G/C (rs 1800795) and −572 G/C (rs1800796) polymorphisms on plasma IL-6 and CRP levels and their associations with hypertension disease in Turkish population we analyzed −174 G/C and −572 G/C polymorphisms and plasma IL-6 and CRP levels in 111 healthy controls and 108 hypertension patients from Adıyaman, Turkey. We determined the genotypes using polymerase chain reaction-restriction fragment length polymorphism and analyzed plasma levels of IL-6 by ELISA and CRP by automated standard biochemical methods. We have found no statistically significant differences between IL-6 gene −174 G/C and −572 G/C genotypes and allelic frequencies and IL-6 and CRP plasma levels and HT (p > 0.05). No CC genotype was found in control subjects for −572 G/C polymorphism. In conclusion, we found relation to −174 G/C and −572 G/C gene variants between neither IL-6 and CRP levels nor hypertension. The −572 G allele and GG genotype are predominant in Turkish population in Adıyaman, Turkey whereas the CC genotype is very rare.     

Genetic polymorphism of human plasminogen in the Japanese population: New plasminogen variants and relationship between plasminogen phenotypes and their biological activities

Summary Genetic polymorphism of human plasminogen in the Japanese population has been described using polyacrylamide gel isoelectric focusing electrophoresis followed by immunofixation techniques. New variants PLG1-1, PLG2-1, and rare 1 were detected. Fibrinolytic activity per milligram plasminogen of each phenotype, except for PLG1-1 and PLG1-1, was within the normal range. The PLG1 component was associated with no or less plasminogen activity, but possessed plasminogen antigen. Gene frequencies calculated from 750 individuals were PLG¹; 0.9560, PLG²; 0.0113, PLG¹; 0.0233, and PLG²; 0.094; respectively. The distribution of phenotypes fitted the Hardy-Weinberg equilibrium. In order to detect the plasminogen phenotypes the immunofixation technique was more suitable than the zymogram technique.     

Baseline frequency of sister-chromatid exchanges in 142 persons of the general Korean population.

Baseline frequencies of sister-chromatid exchange (SCE) were measured in lymphocytes of 142 healthy Koreans ranging in age from newborn infants to the fifties. The overall mean frequency of SCE was 8.78 +/- 0.24/cell. However, highly significant differences were found between individuals. The mean SCE values of the newborn babies and small children less than 10 years old were significantly lower than those of other age groups. No age effect was, however, observed in adolescent and adult subjects. Females had statistically higher SCE levels than males. The mean SCE frequencies of smokers, measured in male subjects more than 10 years old, were slightly, but statistically significantly, higher than those of non-smokers.     

Seroprevalence of 34 human papillomavirus types in the German general population

The natural history of infections with many human papillomavirus (HPV) types is poorly understood. Here, we describe for the first time the age- and sex-dependent antibody prevalence for 29 cutaneous and five mucosal HPV types from 15 species within five phylogenetic genera (alpha, beta, gamma, mu, nu) in a general population. Sera from 1,797 German adults and children (758 males and 1,039 females) between 1 and 82 years (median 37 years) were analysed for antibodies to the major capsid protein L1 by Luminex-based multiplex serology. The first substantial HPV antibody reactions observed already in children and young adults are those to cutaneous types of the genera nu (HPV 41) and mu (HPV 1, 63). The antibody prevalence to mucosal high-risk types, most prominently HPV 16, was elevated after puberty in women but not in men and peaked between 25 and 34 years. Antibodies to beta and gamma papillomaviruses (PV) were rare in children and increased homogeneously with age, with prevalence peaks at 40 and 60 years in women and 50 and 70 years in men. Antibodies to cutaneous alpha PV showed a heterogeneous age distribution. In summary, these data suggest three major seroprevalence patterns for HPV of phylogenetically distinct genera: antibodies to mu and nu skin PV appear early in life, those to mucosal alpha PV in women after puberty, and antibodies to beta as well as to gamma skin PV accumulate later in life.     

Non-cytotoxic variants of the Kid protein that retain their auto-regulatory activity

Kid and Kis are, respectively, the toxin and antitoxin encoded by the parD operon of plasmid R1. The recently solved crystal structure of Kid has revealed that this protein closely resembles the CcdB toxin of plasmid F. In CcdB, the residues involved in toxicity are located at the carboxy-terminal end of the protein. However, an analogous information on the Kid toxin was not available. Here, we have characterized a collection of non-toxic mutants of the Kid protein and identified the residues that affected the toxicity but not the co-regulatory activity of Kid. These are located in two discrete regions of the protein, at the amino and carboxy-terminal ends. Particularly, residues E18 and R85, that are conserved in the Escherichia coli ChpAK and RelE toxins, are affected by amino-acid changes that alter neither the overall structure of the protein nor its state of association, as shown by CD and sedimentation equilibrium analyses. However, thermal denaturation and intrinsic tryptophan fluorescence emission data point to subtle local changes at the N-terminal end of the protein. The implications of these results in the current model on the structure and function of Kid-related bacterial toxins are discussed.     

Functional variants of the human 5-lipoxygenase gene and their genetic diagnosis

Variants in the 5-lipoxygenase (ALOX5) gene are first-line candidate causes for interindividual differences in diseases where leukotrienes play a key role, e.g., inflammatory and immune diseases, atherosclerosis, asthma or the acute respiratory distress syndrome (ARDS). We developed and validated Pyrosequencing™ screening assays for single nucleotide polymorphism (dbSNP-IDs rs4986832, rs4987105, rs2115819, rs3740107, rs1565096, rs2291427, rs10571382, rs2242334, rs2229136, rs3802548), and a capillary electrophoresis assay for the ALOX5 Sp1/Egr1 promoter tandem repeat polymorphism. This selection spans the whole ALOX5 gene range and includes all variants with reported functional associations. A gene structure analysis in DNAs from 187 healthy unrelated Caucasians revealed two haploblocks, one in the promoter and one spanning six SNPs from rs3740107G>A in intron 6 to rs2229136A>G in exon 13. The five-repeat genotype was the most frequent Sp1/Egr1 promoter tandem repeat variant (allelic frequency 84%). These assays and analyses provide a solid basis for future assessments of the genetic modulation of leukotriene production.