Immunological purification and chemical characterization of the group-specific proteins (Gc) from human serum

The group-specific (Gc) proteins have been purified by an immunochemical method from human sera of Gc 1–1 and Gc 2–2 phenotypes. The two electrophoretic components of the Gc 1 protein, Gc 1F and Gc 1S were isolated by electro-focusing. Tryptic peptide maps on cellulose thin layers of Gc 1, Gc 1F, Gc 1S and Gc 2 revealed one peptide specific for Gc 2, another peptide specific for Gc 1 and a third characteristic for Gc 1F. The amino acid composition of these peptides was determined. From these and previous results a hypothesis based on one gene locus is put forward to explain the Gc polymorphism.     

Serum protein polymorphism in Bali (Indonesia)

Serum samples from Bali, obtained in three different ethnic groups and in one isolated village were tested by isoelectric focusing electrophoresis for Gc, Pi, Tf and Hp subtyping. In addition to the three common alleles Gc1F, Gc1S and Gc2, two variants Gc1A1 and Gc1A8 were observed. In the Pi system, five alleles were present: PiM1, PiM2, PiM3, PiM4 and PiX. The Tf variability was exceptional with the presence of eight alleles: TfB1, TfC1, TfC2, TfC3, TfC4, TfC8, TfD1 and TfDchi. For Hp, there were two common alleles Hp1S and Hp1FS and two rare ones: Hp1F and Hp2SS. As expected, the genetic polymorphism is reduced in the isolated community. The anthropological significance of these genetic data is discussed.     

Distribution of group-specific component (Gc) subtypes in several Mongoloid populations of East Asia

The distribution of group-specific component (Gc) subtypes was determined by isoelectric focussing in thin layer polyacrylamide gels of pH range 4 to 6.5, in a group of 2412 individuals from 10 Mongoloid populations of East Asia. The sample comprised 959 Chinese from different localities (Singapore, 249; Malaysia, 347; Taiwan, 246; Hong Kong, 57; Fuzhou mainland, 60), 338 Koreans, 277 Filipinos, 484 Thais, 330 Malays and 24 Indonesians. The Filipinos and Malays had lower frequencies of Gc2 (0.15 and 0.18) compared to other Mongoloid populations (0.23 to 0.32) and the Chinese (0.24 to 0.32). The frequencies of Gc1F varied from 0.39 to 0.49 in the Chinese and 0.35 to 0.52 in other Mongoloid populations. Low frequency of rarer variants was observed in most of the populations. The average frequency of Gc2 was higher in the Japanese (0.26 +/- 0.01) than in the Chinese (0.24 +/- 0.02), and in Mongoloids of East Asia (0.23 +/- 0.01) and South-East Asia (0.17 +/- 0.01). The average frequencies of Gc1F and Gc1S were similar in the Chinese and Japanese, whereas the Mongoloids of South-East Asia had a much higher frequency of Gc1F and a lower frequency of Gc1S than the Chinese, Japanese and East Asian Mongoloid populations.     

Serum protein markers in Chinese schizophrenics - haptoglobin types and transferrin and group-specific component subtypes

Four hundred and thirty-nine Chinese schizophrenic male patients were investigated for the distribution of haptoglobin types; transferrin and group-specific component subtypes. The allelic frequencies of these three polymorphisms in the patient group were compared with those in healthy controls from published series. An excess of Gc2 over Gc1 (chi 2(1) 4.1; P less than 0.05) as well as a lack of Gc1S (chi 2(1) 15.3; P less than 0.001) was observed in schizophrenia. The relative risks of Gc1F, Gc1S and Gc2 have been estimated as 1.12, 0.76 and 1.15, respectively. It appears from this study that the presence of Gc2 renders individuals susceptible while Gc1S offers protection for schizophrenia. No such association was found for the haptoglobin or transferrin polymorphisms.     

A new cathodal Gc variant in Australia

A new cathodal Gc variant and a known rare variant were found in a study of 307 Australian caucasian blood donors, each with a gene frequency of 0.28%. The frequencies of the other alleles were 0.161 (Gc1F), 0.557 (Gc1S) and 0.279 (Gc2), and were comparable with those of two earlier surveys.     

Population studies on PLG group system in the Polish population

Distribution of PLG types was studied in a sample of the Polish population numbering 230 subjects by the method of high-voltage agarose electrophoresis. Of three phenotypes encountered, PLG1, appeared with the frequency of 0.4870, PLG2-1 with 0.4391 and PLG2 with 0.0739. Assuming the hypothesis of PLG controlled by 2 alleles the frequencies of genotypes were calculated as follows: for PLG1 gene -0.71 and for PLG2 gene -0.29. PLG system in the Polish population was confirmed to be in a state of genetic equilibrium. The frequencies of PLG genes in the Polish population do not deviate from the frequencies encountered in other European populations.     

Group-specific component (Gc) subtypes in Gambian and Transkeian populations: a description of a new variant

A total of 270 serum specimens from Keneba and Manduar villages of The Gambia and 126 from Bantu of Transkei were examined for the group-specific component (Gc) phenotypes by isoelectric focusing. Only one individual showed phenotype 2-2 in the Bantu population, and the sub-allele frequencies showed a distribution very characteristic of African populations. A new rare mutation, Gc1C34, was found in heterozygous combination with Gc2 allele. The synthesis of the existing Gc sub-type data was examined for its anthropological implications.     

California serogroup Gc (G1) glycoprotein is the principal determinant of pH-dependent cell fusion and entry

Members of the California serogroup of orthobunyaviruses, particularly La Crosse (LAC) and Tahyna (TAH) viruses, are significant human pathogens in areas where their mosquito vectors are endemic. Previous studies using wild-type LAC and TAH181/57, a highly neurovirulent strain with low neuroinvasiveness (Janssen, R., Gonzalez-Scarano, F., Nathanson, N., 1984. Mechanisms of bunyavirus virulence. Comparative pathogenesis of a virulent strain of La Crosse and an avirulent strain of Tahyna virus. Lab. Invest. 50 (4), 447-455), have demonstrated that the neuroinvasive phenotype maps to the M segment, the segment that encodes the two viral glycoproteins Gn (G2) and Gc (G1), as well as a non-structural protein NSm. To further define the role of Gn and Gc in fusion and entry, we prepared a panel of recombinant M segment constructs using LAC, TAH181/57, and V22F, a monoclonal-resistant variant of LAC with deficient fusion function. These M segment constructs were then tested in two surrogate assays for virus entry: a cell-to-cell fusion assay based on T7-luciferase expression, and a pseudotype transduction assay based on the incorporation of the bunyavirus glycoproteins on an MLV backbone. Both assays demonstrated that Gc is the principal determinant of virus fusion and cell entry, and furthermore that the region delineated by amino acids 860-1442, corresponding to the membrane proximal two-thirds of Gc, is key to these processes. These results, coupled with structural modeling suggesting homologies between the carboxy region of Gc and Sindbis virus E1, suggest that the LAC Gc functions as a type II fusion protein.     

Polymorphism of esterase D in the Polish population.

Distribution of esterase D types was studied in a sample of the Polish population numbering 885 subjects. Frequency of EsDl-1 type was 0.810, EsD2-1 -- 0.174, and EsD2-2 -- 0.16. Frequency of the genes EsD1 and EsD2, which determine this system, were 0.897 and 0.103 respectively. A study of 613 mother-child pairs revealed agreement with the hypothesis of two alleles in the EsD locus. The prevalence of EsD genes in the Polish population was similar to those reported in other European populations.     

UMPK polymorphism in the Polish population

Studies on UMPK polymorphism were carried out in a sample of the Polish population numbering 462 subjects. The occurrence of three phenotypes was confirmed--UMPK 1, UMPK 2-1 and UMPK 2. From distribution of phenotypes, frequencies of determining genes were calculated with the following results: UMPK1-0.9762, UMPK2-0.0238, The usefulness of this system in paternity cases is 1.69%.     

PGM1 subtypes in the Polish population

Frequency of PGM1 subtypes in the sample of the Polish population numbering 197 subjects was determined by the method of isoelectric focusing. Ten subtypes were encountered. Frequencies of genes were calculated from the subtype distribution with the following results: for PGM1+1 0.698, for PGM1-1 0.058, for PGM2+1 0.180 and for PGM2-1 0.064.     

Frequency of genes and heredity of AK types in the Polish population.

Types of the AK groups system were determined in a sample of the Polish population numbering 660 subjects. Two phenotypes were found: AK 1-1 with a frequency of 0-933, and AK 2-1 with a frequency of 0-067. Gene frequencies were AK1 = 0-967 and AK2 = 0-033. Distribution of phenotypes in 62 families with 195 children was consistent with the hypothesis according to which heredity of AK types depends on two codominant alleles.     

Prevalence and inheritance of C3 types in the Polish population.

In a sample of the Polish population numbering 1,458 subjects, the three common types, C3S, C3F and C3FS, were found with frequencies of 0.6790, 0.0295 and 0.2901 respectively, besides two rare variants, C3FO, 7S and C3SO, 25S. Frequencies of C3S and C3F genes were 0.8248 and 0.1746 respectively, and of the CSFO,7 and C3SO,25 genes, 0.0003 each. Distribution of types in 695 mother-child pairs was consistent with the hypothesis that the C3 system depends on a single genetic locus in which codominat alleles are situated. No children of C3S and C3F mothers with opposite homozygous types were encountered. Hereditary character of the C3FO, 7S variant was confirmed by family studies in which the rare C3FO,7 gene, in combination with C3S or C3F genes, occured in three generations.     

Transferrin subtypes in the Polish population

Transferrin subtypes were determined by isoelectric focusing on a thin-layer polyacrylamide gel, using a mixture of ampholine of three pH ranges. In a sample of the Polish population numbering 361 subjects, six Tf subtypes dependent on three alleles Tfcc1, Tfcc2, Tfcc3 were encountered. They occurred with the following frequency: 0.744, 0.212, 0.044. It was found that Tf system in the Polish population was in a good agreement with Hardy Weinberg equilibrium.     

Molecular and phenotypic characteristics of metachromatic leukodystrophy patients from Poland

The occurrence and genotype-phenotype correlations of the eight most common mutations in the arylsulfatase A (ARSA) gene were studied in 43 unrelated Polish patients suffering from different types of metachromatic leukodystrophy (MLD). Screening for mutations p.R84Q, p.S96F, c.459+1G>A, p.I179S, p.A212V, c.1204+1G>A, p.P426L, and c.1401-1411del allowed the identification of 53.5% of the mutant alleles. In the whole investigated group of patients, mutations c.459+1G>A and p.P426L were the most frequent, 19 and 17%, respectively. The prevalence of the third most frequent mutation, i.e. p.I179S (13%), seems to be higher than that in other populations. The incidence of c.1204+1G>A was 5%, which is higher than reported earlier (2%). It seems that p.I179S and c.1204+1G>A are more prevalent in MLD patients from Poland than from other countries. In the group examined by us, mutations p.R84Q, p.S96F, p.A212V, and c.1401-1411del were not detected; thus, 46.5% of MLD alleles remained unidentified. This indicates that other, novel or already described, but rare, mutations exist in Polish population. In late infantile homozygotes for c.459+1G>A and one homozygote for c.1204+1G>A, first clinical symptom was motor deterioration. In adult homozygotes for p.P426L, the disease onset manifested as gait disturbances, followed by choreoathetotic movements, difficulties in swallowing, dysarthria, tremor, and nystagmus. In the carriers of the p.I179S mutation, the hallmark of the clinical picture was psychotic disturbances.     

Analysis of LRRK 2 G 2019 S and I 2020 T mutations in Parkinson's disease

Mutations in the leucine-rich repeat kinase 2 (LRRK 2), encoding dardarin protein, have been demonstrated to be linked to autosomal dominant Parkinson's disease (PD). In the present study the entire exon 41 of LRRK 2 gene was evaluated in a series of 174 PD patients recruited from Polish population, aged at the time of diagnosis 54.0+/-39.1 years, 21 of them had positive family history of PD with mean onset of the disease of 51.9+/-11.7 years as well as in 190 healthy controls aged 73.7+/-6.0 years. The mutations were evaluated by direct sequencing for mutations in exon 41 of LRRK 2 gene. In the studied patients no known mutations in exon 41 of LRRK 2 gene, including G 2019 S and I 2020 T were found, both in PD patients as well as in the controls. It can be concluded that the G 2019 S and I 2020 T mutations in exon 41 of LRRK 2 gene are rare causes of Parkinson disease in a Polish population.     

Polymorphism of C3 component of complement in the Polish population. I. Population and family studies

In a sample of the Polish population numbering 4741 subjects, the three common types C3S, C3F and C3FS and 15 phenotype variants were found with frequencies 0.0046. The frequencies of C3S and C3F genes determining the common types were 0.8227 and 0.1750, respectively. Examination of 40 newborns and their mothers has revealed that C3 types are formed during the fetal life. The results of studies on 76 families with 157 children and 2332 mother-child pairs have confirmed that 3C3 types are determined by a single genetic locus in which codominant autosomal alleles are situated.     

The phosphoglucomutase group system of human erythrocytes

Frequency of PGM1 phenotypes and their corresponding genes in the Polish population was determined in two samples: in 760 adults and 240 children. The frequency of the PGM1 1 gene in adults was 0-748, and in children 0-765. A statistically significant deficiency of heterozygotes was found in adults. Heredity of the phosphoglucomutase system was studied in 52 families with 162 children, in 223 mother-child pairs, and in 73 twin pairs of the same sex. In all groups, phenotypes of PGM1 agreed with the hypothesis of heredity, assuming a pair of alleles of the PGM1 system. In the parent combinations PGM1 1-1 X PGM1 2-1 a deficiency of PGM1 2-1 children was found. Analysis of linkage of genes of the PGM1 system with eight group systems provided data indicating a possibility of linkage of the PGM1 system with the Rh system. The theoretical usefulness of the PGM1 system in paternity investigations in the Polish population was estimated to be 14-24%.     

Polymorphism of C3 component of complement in the Polish population. II. Rare phenotypes in C3 system

In a sample of the Polish population including 4741 adults, 15 phenotype variants were found in 22 of them. These variants are determined by 12 rare alleles of the mean frequency 0.0023. Family studies of several probands with C3 phenotype variants have confirmed their genetic determination. They have been observed to be heterozygotes in which beside one common gene, rare codominant alleles are situated. Studies on polymorphism of C3 component carried out on numerous populations, allowed the discovery of new phenotype variants within the C3 group system. Family studies have confirmed their hereditary character and that they are determined by the alleles codominant in relation to the commonly occurring C3S and C3F. The paper presents the results of studies on the rare C3 phenotype variants encountered in the Polish population.     

Effect of vitamin D–binding protein genotype on the development of asthma in children

BackgroundPotential vitamin D–related influences on inflammatory diseases such as asthma are controversial, including the suggestion that vitamin D insufficiency is associated with increased asthma morbidity. Vitamin D–binding protein transports vitamin D metabolites in the circulation. Single nucleotide polymorphisms in the GC gene encoding vitamin D–binding protein are associated with circulating vitamin D metabolite levels in healthy infants and toddlers.ObjectiveTo test the hypothesis that GC single nucleotide polymorphisms encoding the D432E and T436K variants predict subsequent development of asthma in healthy children.MethodsA retrospective medical record review was performed to determine the development of asthma in 776 children in whom GC genotype, vitamin D–binding protein concentration, and circulating 25-hydroxyvitamin D had been determined at 6 to 36 months of age. Demographic and detailed current clinical data were collected and criteria for asthma were recorded.ResultsGC genotype was available for 463 subjects. After an initial analysis of all subject data, the analysis was limited to the predominant Hispanic population (72.1%) to minimize potential confounding effects of ethnicity. Asthma was diagnosed in 87 children (26%). Subjects with the GC genotype encoding the ET/ET (Gc1s/Gc1s) variant had lower odds of developing asthma, representing a protective effect compared with subjects with the DT/DT (Gc1f/Gc1f) variant.ConclusionIn the Hispanic population of inner-city New Haven, Connecticut, the ET/ET (Gc1s/Gc1s) genotype of vitamin D–binding protein might confer protection against the development of asthma compared with the wild-type genotype DT/DT (Gc1f/Gc1f).