A new polymorphic variant of human complement factor I

Summary Sera from 305 individuals were typed for factor I, and a new variant, tentatively designated FI^* C, was found. All other samples were FIB except for seven samples from Chinese that were of the FI AB phenotype. This suggests that polymorphism of factor I may be rare in Caucasians.     

Polymorphism of 6-PGD in South Korea: a new genetic variant 6-PGD Korea

Summary During population genetic studies in Korea a new variant in the 6-phosphogluconate (6-PGD) system preliminary called 6-PGD^Korea was observed.     

A genetic survey in four Mongoloid populations of the Garo Hills, India

Four Mongoloid populations, viz., Garo , Hajong , Rabha and Koch, belonging to the Tibetoburman language family of Garo Hills, India, were examined for blood types ( A1A2BO , Rh, MN), secretor factor, ability to taste PTC and cerumen types. Gene A1 is more frequent than B in Hajong and Rabha . Garo shows a higher frequency of gene B, Koch also shows a little higher frequency of gene B than A. R1 is the commonest chromosome in all the groups followed by R2. Frequency of gene M is very high in all these populations. In respect of ABH secretion in saliva, there is preponderance of the secretor gene. Incidence of non- taster gene is somewhat lower in them. Dry cerumen gene is frequent in these Mongoloid groups. In general, the Garo Hills populations show closer affinity to the Mongoloids of Northeast India in respect of gene frequencies.     

Polymorphism rs7214723 in CAMKK1: a new genetic variant associated with cardiovascular diseases

Cardiovascular diseases (CVDs) are the leading cause of deaths worldwide. CVDs have a complex etiology due to the several factors underlying its development including environment, lifestyle, and genetics. Given the role of calcium signal transduction in several CVDs, we investigated via PCR-restriction fragment length polymorphism (RFLP) the single nucleotide polymorphism (SNP) rs7214723 within the calcium/calmodulin-dependent kinase kinase 1 (CAMKK1) gene coding for the Ca²⁺/calmodulin-dependent protein kinase kinase I. The variant rs7214723 causes E375G substitution within the kinase domain of CAMKK1. A cross-sectional study was conducted on 300 cardiac patients. RFLP-PCR technique was applied, and statistical analysis was performed to evaluate genotypic and allelic frequencies and to identify an association between SNP and risk of developing specific CVD. Genotype and allele frequencies for rs7214723 were statistically different between cardiopathic and several European reference populations. A logistic regression analysis adjusted for gender, age, diabetes, hypertension, BMI and previous history of malignancy was applied on cardiopathic genotypic data and no association was found between rs7214723 polymorphism and risk of developing specific coronary artery disease (CAD) and aortic stenosis (AS). These results suggest the potential role of rs7214723 in CVD susceptibility as a possible genetic biomarker.     

Polymorphism of human complement component C4

An assessment has been made of the polymorphism of human complement component C4 by comparing derived amino acid sequences of cDNA and genomic DNA with limited amino acid sequences. In all, one complete and six partial sequences have been obtained from material from three individuals and include two C4A and two C4B alleles. Differences were found between the 4 alleles from 2 loci in only 15 of the 1722 amino acid residues, and 12 lie within one section of 230 residues, which in 1 allele also contains a 3-residue deletion. In three variable positions, an allelic difference in one C4 type was common to the other types. Three nucleotide differences were found in four introns. In spite of marked differences in their chemical reactivity, the many allelic forms appear to differ in less than 1% of their amino acid residue positions. This unusual pattern of polymorphism may be due to recent duplication of the C4 gene, or may have arisen by selection as a result of the biological role of C4, which interacts in the complement sequence with nine other proteins necessitating conservation of much of the surface structure.     

Polymorphism of the fourth component of complement in Turks

An analysis of polymorphism in the fourth component of human complement (C4) was performed on EDTA-plasma from 142 unrelated, randomly selected Turks without collagen-vascular disease or recurrent infections. Plasma samples treated with neuraminidase and carboxypeptidase-B were subjected to high-voltage agarose gel electrophoresis followed by immunofixation. C4B allotypes were further detected in some samples by Western blots with monoclonal antibody 1228 (anti-C4B/Ch1 reactivity). The frequencies of C4A and C4B alleles were determined. Allele C4B*5, which has been found to be relatively common in Asian (Oriental) populations, was not detected in this study. No specific predilection could be noted among the rare variants. C4A*3-C4B*1 was the most common haplotype (n = 40/142, or 28%) but was found less frequently than in Caucasian populations. This finding may be the result of the limited number of samples examined. C4A and/or C4B null allotypes were seen in 49 of 142 (34.6%) subjects. The most frequent C4 null allotype seen was C4B null (37/142, or 26%): 28 subjects had one C4B null allele; 1 had a homozygous deficiency of C4B (C4B*QO, *QO) and 7 had C4A*QO C4B*QO, a double heterozygous haplotype. Frequencies of homozygous haplotype C4A*Q0-C4B*Q0 in the population studied were found to be 0.007. The results of this study demonstrate that the genetic composition of the Turkish population exhibits both similarities and differences with the European population, and ranges between Caucasian and Mongoloid (Asian) populations.     

Polymorphism of the third component of human complement

Genetic polymorphism of the third component of human complement (C3) has been considered as a powerful marker for population genetics. Some studies on the distribution of gene frequencies have been performed among numerous populations all over the world. This review takes stock of population genetic studies reported up to now and points out some remarks on the distribution of the observed allelic frequencies.     

C4A7: a new variant of human complement C4

A rare variant of complement C4 was found in 2 related individuals. It has the most anodic mobility found to date, no hemolytic activity detected by the overlay technique and a Bgl II RFLP pattern very similar to that of the C4A6 type.     

Polymorphism of the second component of complement (C2) in Graves' disease

The polymorphism of C2 was studied by isoelectric focussing in 60 patients with Graves' disease and compared to 800 control sera. No difference in gene frequencies was observed.     

Albumin Paris 2: a new genetic variant distinguished by isoelectric focusing.

Until recently, the characterization of genetic variants of human serum albumin was performed by electrophoretic typing prior to the determination of their amino acid substitutions. We describe a procedure using isoelectric focusing in the presence of urea for the analysis of the genetic variation of albumin. This procedure allowed a clear distinction of a new variant, previously found to be identical with albumin Sondrio according to its relative electrophoretic mobilities at 3 pHs. This new variant, the third rare albumin allotype identified in the Ile-de-France region, was called albumin Paris 2.     

Characteristics of Mongoloid and neighboring populations based on the genetic markers of human immunoglobulins

Summary Since the discovery in 1966 of the Gm ab3st gene, which characterizes Mongoloid populations, the distribution of allotypes of immunoglobulins (Gm) among Mongoloid populations scattered from Southeast Asia through East Asia to South America has been investigated, and the following conclusions can be drawn: 1. Mongoloid populations can be characterized by four Gm haplotypes, Gm ag, axg, ab3st, and afb1b3, and can be divided into two groups based on the analysis of genetic distances utilizing Gm haplotype frequency distributions: the first is a southern group characterized by a remarkably high frequency of Gm afb1b3 and a low frequency of Gm ag, and the second, a northern group characterized by a high frequency of both Gm ag and Gm ab3st but an extremely low frequency of Gm afb1b3. 2. Populations in China, mainly Han but including minority nationalities, show remarkable heterogeneity of Gm allotypes from north to south and contrast sharply to Korean and Japanese populations, which are considerably more homogenous with respect to these genetic markers. The center of dispersion of the Gm afb1b3 gene characterizing southern Mongoloids has been identified as the Guangxi and Yunnan area in the southwest of China. 3. The Gm ab3st gene, which is found with its the highest incidence among the northern Baikal Buriats, flows in all directions. However, this gene shows a precipitous drop from mainland China to Taiwan and Southeast Asia and from North to South America, although it is still found in high frequency among Eskimos, Koryaks, Yakuts, Tibetans, Olunchuns, Tungus, Koreans, Japanese, and Ainus. On the other hand, the gene was introduced into Huis, Uyghurs, Indians, Iranians, and spread as far as to include Hungarians and Sardinians in Italy. On the basis of these results, it is concluded that the Japanese race belongs to northern Mongoloids and that the origin of the Japanese race was in Siberia, and most likely in the Baikal area of the Soviet Union.     

Human chromosomal polymorphism. I. Chromosomal Q polymorphism in Mongoloid populations of central Asia

Summary A comparative study of frequencies and types of Q-polymorphic variants in seven autosome pairs (3, 4, 13–15, 21, and 22) was performed in three steppe Mongoloid populations of Central Asia (Kazakhs, Dunghans, Mongolians) and three highland Kirghiz populations of Pamir and Tien-Shan. The three steppe Mongoloid populations showed statistically significant homogeneity both in the frequency of Q-polymorphic variants and the distribution of homo- and heteromorphs, with complete agreement of observed frequencies with those theoretically predicted by the law of Hardy-Weinberg. Similar homogeneity was revealed in the three highland Kirghiz populations of Pamir and Tien-Shan. However, comparative analysis of highland and steppe Mongoloids revealed significant differences in the following variables: (1) mean number of Q variants per individual, 2.50 and 3.49 in the highland and steppe populations, respectively; (2) frequency of Q variants in 7 of the 12 autosomes studied; and (3) distribution of homo- and heteromorphs in four autosomal pairs (13–15, 21) with a preponderance of individuals with increased homomorph (-/-) frequency in highlanders.The following questions are discussed: (1) the possible selective value of chromosomal Q-heterochromatin material in the adaptation of human populations to extreme environmental factors, in particular to the high-altitude environment of Pamir and Tien-Shan; (2) the existence of intraracial heterogeneity in Mongoloids living in different ecological zones; and (3) the possible taxonomic value of Q-variant inversion in chromosome 3.     

Polymorphism of the sixth component of complement (C6) in the dog

Isoelectric focusing was used to identify five alleles at the locus determining the production of the sixth component of complement (C6) in the dog. Four of these alleles,C6 ¹, C6², C6⁴,andC6 ⁵,were studied in family pedigrees and shown to be inherited in a codominant autosomal fashion. All alleles except forC6 ⁴occurred commonly in the multiple breeds tested. This investigation was supported by Grant HL 17265 awarded by the National Institute of Heart, Lung, and Blood Diseases, DHEW, and by Grants CA 18105 and CA 31787 awarded by the National Cancer Institute.     

A new complement factor B variant (BF S075) in Japanese

A new slow-moving variant of the complement factor B, named BF S075, was found in a Japanese patient with cerebral thrombosis and urticaria. The variant was inherited in a codominant manner. The protein concentration and functional hemolytic activity of the complement factor B in the patient's serum were within normal limits. The BF S075 is the fourth rare BF variant found in the Japanese population.     

A new genetic variant of galactose-1-phosphate uridyl transferase

Summary The enzyme galactose-1-phosphate uridyl transferase (E.C. 2.7.7.12), which has an important function in the metabolism of galactose, exists in multiple molecular forms. The different phenotypes are genetically determined. They can be distinguished according to their electrophoretic mobility. The enzymatic activity of the different gene products varies within certain limits. A new phenotype of the enzyme has been detected in the red cells of a healthy individual. The electrophoretic migration of this phenotype is slower compared to the wild type and its enzymatic activity is lower, but still sufficient as not to cause galactosemia. An extensive family study revealed that the rare gene is inherited according to mendelian law. Independently the same gene product has been detected in two other, nonrelated individuals out of a total of 1668 samples tested. The gene frequency can therefore be estimated to 0.0009 in the Swiss population. We suggest that the new type be called Berne variant of galactose-1-phosphate uridyl transferase.     

Structure of compstatin in complex with complement component C3c reveals a new mechanism of complement inhibition

Undesired complement activation is a major cause of tissue injury in various pathological conditions and contributes to several immune complex diseases. Compstatin, a 13-residue peptide, is an effective inhibitor of the activation of complement component C3 and thus blocks a central and crucial step in the complement cascade. The precise binding site on C3, the structure in the bound form, and the exact mode of action of compstatin are unknown. Here we present the crystal structure of compstatin in complex with C3c, a major proteolytic fragment of C3. The structure reveals that the compstatin-binding site is formed by the macroglobulin (MG) domains 4 and 5. This binding site is part of the structurally stable MG-ring formed by domains MG 1-6 and is far away from any other known binding site on C3. Compstatin does not alter the conformation of C3c, whereas compstatin itself undergoes a large conformational change upon binding. We propose a model in which compstatin sterically hinders the access of the substrate C3 to the convertase complexes, thus blocking complement activation and amplification. These insights are instrumental for further development of compstatin as a potential therapeutic.