Gc subtyping in Malaysians and in Indonesians from North Sumatra

Summary Malays, Chinese and Indians from peninsular Malaysia; Ibans and Bidayuh from Sarawak state, Northern Borneo; and Bataks, Minangkabau and Javanese from North Sumatra, Indonesia, were subtyped for Gc (group-specific component) by polyacrylamide gel isoelectric focusing. All eight populations investigated were found to be polymorphic for three common alleles, Gc^IF, Gc^IS and Gc².     

Group-specific component (Gc) subtypes in the Chinese population of Hong Kong

Summary The distribution of Gc subtypes in a sample of the Chinese population of Hong Kong was studied using isoelectric focusing followed by immunofixation. A sensitive modification of this technique is described. Nine distinct phenotypes were observed which appear to result from the three common alleles Gc ^IF, Gc ^IS, and Gc ², which are found in most populations. The respective gene frequencies were 0.494, 0.258, and 0.247. In addition, two rare phenotypes were observed which appear to be due to a rare allele tentatively identified as Gc ^2G2.     

Human transferrin (Tf) and group-specific component (Gc) subtypes in Tunisia

Summary Simultaneous subtyping of two genetic markers—group-specific component (Gc) and transferrin (Tf)—by electrofocusing enabled us to compute the following gene frequencies for the Tunisian population: Gc ^IS .0.525; Gc ^IF , 0.260; Gc ², 0.215; Tf ^CI , 0.770; Tf ^C2 , 0.215; Tf ^D1 , 0.015.The frequencies of Tf ^D , Tf ^C2 , and Gc ¹ are higher than those found in Caucasoid populations and can be explained by Negroid contribution. A selective advantage related to the metabolic role of this vitamin D-binding protein does not seem very likely for any particular Gc type or subtype. It is postulated that the differences in the frequencies of the Gc alleles might be related to selective advantage for genes belonging to other genetic systems originally closely linked to either Gc ¹ or to Gc ² alleles.This work was supported in part by the Faculté de Pharmacie et de Médecine Dentaire of Monastir and by a grant from the Ambassade de France in Tunisia     

Distribution of the group specific (Gc) serum component in the populations of the Markham Valley, New Guinea

The distribution of the Gc phenotypes was determined by immunoelectrophoresis amongst 486 inhabitants of nine villages of the Markham River Valley of New Guinea. The overall gene frequencies were Gc¹, 0.538; Gc², 0.351; Gc^Aborigine, 0.112. Gc^Aborigine occurred in all the villages, its frequency ranging from 0.041 to 0.187. The Gc² gene frequency also varied widely ranging from 0.167 to 0.491. No correlation could be found between altitude and the Gc distribution and there was an overlap in the gene frequencies between the Austronesian and non-Austronesian-speaking villages.     

Evolutionary conservation of equine gc alleles and of Mammalian gc/albumin linkage

Ancient origin of the equine vitamin D binding protein (Gc) polymorphism is suggested by the finding of two alleles, Gc^F and Gc^S, in each of three equine subgenera, Equus, Asinus and Hippotigris. The equine Gc and albumin loci are closely linked (lod score = 6). Although no recombinants were observed, the data are not inconsistent with a map distance similar to the 2 centimorgans reported for the human albumin/Gc linkage relationship. Gametic association between the Gc^F and Alb^F alleles appears probable in the American Standardbred horse, perhaps as a result of population structure. Since Gc and albumin are both polymorphic in rodents and possibly other orders, this linkage group will be useful for studies of the evolution of mammalian linkage groups, as well as for a comparison of meiotic recombination frequencies and linkage disequilibria in different species.     

Analysis of the Gc polymorphism in human populations by isoelectrofocusing on polyacrylamide gels. Demonstration of subtypes of the Gc1 allele and of additional Gc variants

Summary For the study of the group-specific component (Gc) system, serum samples were examined by polyacrylamide gel electrophoresis and by a newly developed immunofixation isoelectrofocusing procedure. Thereby, a greater extent of polymorphic variation was revealed than was known previously. The allele Gc¹ could be subdivided into the alleles Gc^1F and Gc^1S. The distribution of Gc¹ subtypes was very different in three populations (Pygmies, Amerindians, and Pyreneans) examined. New variants of the Gc¹ and Gc² genes were also described in the Amerindian and in the Pygmy population, respectively.     

Serum protein polymorphisms in a village community from the Gambia,West Africa (Hp,Tf, and Gc)

Summary Serum samples from 857 inhabitants of the village of Keneba, The Gambia, West Africa, were examined by means of polyacrylamide gel electrophoresis. In 203 cases no haptoglobin could be detected, whilst in the remaining 654 samples the three common haptoglobin phenotypes were found with gene frequencies of 0.651 (Hp¹) and 0.349 (Hp²). The D₁ transferrin variant gene was found with a frequency of 0.025. In the serum Gc system the fast variant Gc-Ab was detected, the gene frequencies being: Gc¹, 0.943; Gc², 0.044; and Gc^Ab, 0.013.     

The distribution of Gc subtypes among the Mongoloid populations

The polymorphism of Gc (group-specific components) has been investigated for a series of 3,160 individual samples from 11 Mongoloid populations in Asia and North and South America by isoelectric focusing on polyacrylamide gels. The samples fall into six Gc phenotypes which can be explained by the three common alleles, Gc^1F, Gc^1S, and Gc², together with several variant phenotypes explained as the heterozygotes for the three common alleles. The distribution of Gc^1F suballele appears to be considerably different from population to population among Mongoloids, ranging from 0.105 (Machiguenga Indans, Peru) to 0.609 (Kadazan, Borneo). A clear geographic cline from Southeast Asia into South America in Gc^1F allele was observed in the populations. In general, Gc^1F allele frequencies are lower in European populations and higher in African populations. The range of variability in the Gc^1F values observed among the Asiatic populations is between the Africans and the Europeans.     

Serumprotein polymorphisms in Iran

Summary The results of a population genetic investigation on Iranians are given and compared to the results obtained on other populations from Southwestern and Southern Asia. Our total material from Iran comprises n=1020 nonrelated male and female individuals of different age. The following serum groups have been typed: Hp, Gc, Gm, and Inv. In general there exist no remarkable age or sex differences in the distribution of phenotypes and alleles (the only exception: sex differences in the distribution of the Gm (7)-phenotype). The regional distribution of phenotypes and alleles yield no marked differences, too, apart from the Invphenotypes, however. For the total material of Iran the following alleles frequencies could be calculated: Hp¹=0.3045, Hp²=0.6595, Gc²=0.3405; Gm¹=0.1780, Gm^1,2=0.0537, Gm^1,5=0.0632, Gm⁵=0.7051. The Gm (7)-phenotype turned out to be 36.6%; the Inv (1)-phenotype amounts to 25.6%. Comparing with other populations, especially Pakistani and Indian samples, some heterogeneity in the distribution of phenotypes and alleles within Southwestern and Southern Asia was to be demonstrated. Some distributional trends of alleles frequencies shall be mentioned here: the increase of Hp², Gc¹, and Gm¹ alleles from West towards East, and in the opposite direction the decrease of Hp¹, Gc², and Gm⁵ alleles. Selective acting forces are supposed to be most important factors for this. D77     

Zur Häufigkeit der Serumprotein-Polymorphismen Hp,Gc, Gm,InV und Lp in Griechenland

The authors report the frequencies of Hp-, Gc-, Gm-, InV-, and Lp-phenotypes and alleles in a Greek sample of 218 unrelated adult males and females. The following gene-frequencies were obtained: Hp¹=.2850, Hp²=.7150; Gc¹=.7590, Gc²=.2410; Gm¹=.1555, Gm^1,2=.1015, Gm¹²=.7430. The phenotype InV (1) was found to be 14.6%. Lp (ax)-typing showed 17.0% strong positive individuals, 9.7% weak positive ones, and 73.3% negatives. According to Speiser and Pausch (1965) this may be interpreted as the following phenotypes distribution: Lp (a+x+)=17.0%, Lp(a+x-)=9.7%, and Lp(a-x-)=73.3%. Our data differ somewhat from data obtained by other authors, which seems to indicate heterogeneity in the distribution of at least Hp- and Gm-phenotypes within the Greek population. This is project to further research.     

Effects of Zn2+ on the activity and binding of the mitochondrial ATPase inhibitor protein,IF1

Zn²⁺ caused a noninhibitory binding of IF₁ to mitochondrial membranes in both rabbit heart SMP and intact rabbit heart mitochondria. This Zn²⁺-induced IF₁ binding required the presence of at least trace amounts of MgATP and was essentially independent of pH between 6.2 and 8.2. Addition of Zn²⁺ after the formation of fully inhibited IF₁-ATPase complexes very slowly reversed IF₁-mediated ATPase inhibition without causing significant IF₁ release from the membranes. When Zn²⁺ was added during the state 4 energization of ischemic mitochondria in which IF₁ was already functionally bound, it slowed somewhat energy-driven ATPase activation. This slowing was probably due to the fairly large depressing effect Zn²⁺ had upon membrane potential development, but Zn²⁺ did not decrease the degree of ATPase activation eventually reached at 20 min of state 4 incubation. Zn²⁺ also preempted normal IF₁ release from the membranes, causing what little inhibitor that was released to rebind to the enzyme in noninhibitory IF₁-ATPase complexes. The data suggest that IF₁ can interact with the ATPase in two ways or through two kinds of sites: (a) a noninhibitory interaction involving a noninhibitory IF₁ conformation and/or and IF₁ docking site on the enzyme and (b) an inhibitory interaction involving an inhibitory IF₁ conformation and/or a distinct ATPase activity regulatory site. Zn²⁺ appears to have the dual effect of stabilizing the noninhibitory IF₁-ATPase interaction and possibily a noninhibitory IF₁ conformation while concomitantly preventing the formation of an inhibitory IF₁-ATPase interaction and possibly an inhibitory IF₁ conformation, regardless of pH. While the data do not rule out direct effects of Zn²⁺ on either free IF₁ or the free enzyme, they suggest that Zn²⁺ cannot interact readily with either the inhibitor or the enzyme once functional IF₁-ATPase complexes are formed.     

Serum Gc system in liver cirrhosis and hepatoma

Summary Serum Gc polymorphism was studied in 85 patients with liver cirrhosis, in 65 with cirrhosis plus hepatoma, and in 40 with hepatoma without cirrhosis. Six hundred unrelated healthy Greeks served as controls. The Gc 1-1 phenotype was found more frequently in patients who had cirrhosis with or without hepatoma but the incidence of the Gc¹ gene was significantly higher in patients with cryptogenic-HBsAg negative cirrhosis. On the other hand, the Gc 2-2 phenotype was found about three times more frequently in patients who had hepatoma without cirrhosis, and the incidence of the Gc² gene was significantly higher in the same group than in the controls. Consequently, it could be surmised that the Gc¹ and the Gc² genes predispose, under the influence of various factors, the development of cryptogenic cirrhosis and hepatoma without cirrhosis, respectively.     

Gc types in one Indian group and one Mestizo Mexican group

Summary The distribution of Gc types was investigated in an Indian group residing in Cuetzalan, Puebla, and in a Mestizo group from Mexico City. Gc¹ and Gc² gene frequencies were 0.862 and 0.138 in Cuetzalan, and 0.858 and 0.142 in Mexico City. These figures are similar to those obtained by other authors in one Northeastern Mexican City. A literature review showed that there appears to be a pattern of high Gc²-frequency in most Brazilian Indians (above 0.3) in contrast to a low frequency (below 0.2) in most other Amerindian groups studied.     

A faster migrating Gc-variant: Gc Darmstadt

Summary In three members of a family from Darmstadt (Germany) a faster migrating Gc variant has been observed. The variant phenotypes have been examined by routine immunoelectrophoresis (Fig. 1), by immunoelectrophoresis with prolonged separation times and with Gc-monospecific antisera (Fig. 2), by polyacrylamide gel electrophoresis (Fig. 3), and by antigen-antibody crossed electrophoresis (Fig. 4). By antigen-antibody crossed electrophoresis the new Gc variant was clearly distinguishable from the Gc Aborigine and from the Gc Chippewa variant. The variant was named Gc Darmstadt (Gc D). Gc Darmstadt has an electrophoretic migration rate intermediate between Gc Ab and Gc 1. In two sibs the type Gc D-2 was observed, the daughter of one of these sibs had the type Gc D-1. The analysis of several members of this family provided only limited information on the mode of inheritance of Gc Darmstadt (Fig. 5). Gc Darmstadt appears to be determined by a gene Gc^D which may be allelic to Gc¹ and Gc².

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Zusammenfassung Bei drei Angehörigen einer Familie aus Darmstadt (Deutschland) wurde eine schneller wandernde Gc-Variante beobachtet. Die neue Variante, die eindeutig von Gc Aborigine und Gc Chippewa unterschieden werden kann, wurde Gc Darmstadt (Gc D) genannt. Bei elektrophoretischer Auftrennung liegt Gc Darmstadt zwischen Gc Ab und Gc 1. Gc Darmstadt ist sehr wahrscheinluch durch ein Gen Gc^D bedingt, das ein Allel zu Gc¹ und Gc² ist.

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Supported by U.S.-PHS Grant AM 11796 and aided by a grant from the Deutsche Forschungsgemeinschaft, Bad Godesberg.     

The role of the ATPase inhibitor factor 1 (IF1) in cancer cells adaptation to hypoxia and anoxia

The physiological role of the mitochondrial ATP synthase complex is to generate ATP through oxidative phosphorylation. Indeed, the enzyme can reverse its activity and hydrolyze ATP under ischemic conditions, as shown in isolated mitochondria and in mammalian heart and liver. However, what occurs when cancer cells experience hypoxia or anoxia has not been well explored. In the present study, we investigated the bioenergetics of cancer cells under hypoxic/anoxic conditions with particular emphasis on ATP synthase, and the conditions driving it to work in reverse. In this context, we further examined the role exerted by its endogenous inhibitor factor, IF₁, that it is overexpressed in cancer cells. Metabolic and bioenergetic analysis of cancer cells exposed to severe hypoxia (down to 0.1% O₂) unexpectedly showed that Δψ_m is preserved independently of the presence of IF₁ and that ATP synthase still phosphorylates ADP though at a much lower rate than in normoxia. However, when we induced an anoxia-mimicking condition by collapsing Δμ_Η⁺ with the FCCP uncoupler, the IF₁-silenced clones only reversed the ATP synthase activity hydrolyzing ATP in order to reconstitute the electrochemical proton gradient. Notably, in cancer cells IF₁ overexpression fully prevents ATP synthase hydrolytic activity activation under uncoupling conditions. Therefore, our results suggest that IF₁ overexpression promotes cancer cells survival under temporary anoxic conditions by preserving cellular ATP despite mitochondria dysfunction.     

Gc subtypes in the middle east: Report on an Arab Moslem population from Israel

Gc subtypes were determined by isoelectrofocusing and immunofixation on 342 blood samples from an Arab Moslem population in Israel. Observed allele frequencies were: Gc^1F 0.2120, Gc^1S 0.6023, and Gc² 0.1857. Those are similar to formerly reported frequency data for other Middle Eastern populations. A discriminant analysis, performed on data from 35 populations, resulted in a satisfactory classification of population groups related through geographic and racial origin.     

Suppression of UV- and interferon-α-refractoriness by antipain in human IFr cells established from RSa cells sensitive to both stimuli

The human cell line IF^r is a variant with an increased resistance to cell proliferation inhibition (CPI) by human interferon (HuIFN)-α, established from RSa cells with unusually high-sensitivity to CPI. IF^r cells were later found to have increased resistance to the cell-killing effects of far-ultraviolet (UV) irradiation. Here, in cell lysates extracted from UV-irradiated IF^r cells but not in those from irradiated RSa cells, fibrinolytic protease activity was found to be elevated promptly and transiently after irradiation. Treatment of IF^r cells with HuIFN-α alone also resulted in the elevation of protease activity, but not that of RSa cells. Both the activity elevated after UV irradiation and after HuIFN-α treatment was inhibited to the greatest extent by antipain in vitro. Moreover, the refractoriness of IF^r cells to UV cell-killing and to HuIFN-α CPI was suppressed by culturing with medium containing antipain immediately after UV irradiation or during HuIFN-α exposure. In similarly treated RSa cells, there was no modulation of UV- or HuIFN-α-susceptibility. These comparative characteristics between the two cell lines suggested that antipain-sensitive proteases and/or cellular functions may be involved in increased resistance to UV and HuIFN-α of IF^r cells. © 1996 Wiley-Liss, Inc.     

Identification of a Conserved Calmodulin-Binding Motif &;#x220A; the Sequence of F<Subscript>0</Subscript>F<Subscript>1</Subscript>ATPsynthase Inhibitor Protein

The natural inhibitor proteins IF₁ regulate mitochondrial F₀F₁ATPsynthase in a wide range of species. We characterized the interaction of CaM with purified bovine IF₁, two bovine IF₁ synthetic peptides, as well as two homologous proteins from yeast, namely IF₁ and STF₁. Fluorometric analyses showed that bovine and yeast inhibitors bind CaM with a 1:1 stoichiometry in the pH range between 5 and 8 and that CaM-IF₁ interaction is Ca²⁺-dependent. Bovine and yeast IF₁ have intermediate binding affinity for CaM, while the K_d (dissociation constant) of the STF₁-CaM interaction is slightly higher. Binding studies of CaM with bovine IF₁ synthetic peptides allowed us to identify bovine IF₁ sequence 33–42 as the putative CaM-binding region. Sequence alignment revealed that this region contains a hydrophobic motif for CaM binding, highly conserved in both yeast IF₁ and STF₁ sequences. In addition, the same region in bovine IF₁ has an IQ motif for CaM binding, conserved as an IQ-like motif in yeast IF₁ but not in STF₁. Based on the pH and Ca²⁺ dependence of IF₁ interaction with CaM, we suggest that the complex can be formed outside mitochondria, where CaM could regulate IF₁ trafficking or additional IF₁ roles not yet clarified.     

Über die Verteilung der Gc-Typen in Südniedersachsen nebst Literaturübersicht über die Allelenhäufigkeit im deutschen Sprachgebiet

Zusammenfassung An den Seren von 1733 Probanden wurden Gc-Bestimmungen vorgenommen. Es fand sich eine Gc¹-Genhäufigkeit von 0,7185 in Südniedersachsen. Diese Häufigkeit liegt etwas unter dem Durchschnitt im deutschen Sprachgebiet (n=15001) mit 0,7277.

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1733 serum samples from inhabitants of South-Niedersachsen have been submitted to Gc type determination. A Gc¹ gene frequency of 0,7185 was found in this material, which is a little less than the average value of 0,7277 (n=15001) in the total region of German language.

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Direktor: Prof. Dr. med. P. E. Becker     

Regulation of mitochondrial structure and function by the F1Fo-ATPase inhibitor protein, IF1

When mitochondrial respiration is compromised, the F₁F_o-ATP synthase reverses and consumes ATP, serving to maintain the mitochondrial membrane potential (Δψ_m). This process is mitigated by IF₁. As little is known of the cell biology of IF₁, we have investigated the functional consequences of varying IF₁ expression. We report that, (1) during inhibition of respiration, IF₁ conserves ATP at the expense of Δψ_m; (2) overexpression of IF₁ is protective against ischemic injury; (3) relative IF₁ expression level varies between tissues and cell types and dictates the response to inhibition of mitochondrial respiration; (4) the density of mitochondrial cristae is increased by IF₁ overexpression and decreased by IF₁ suppression; and (5) IF₁ overexpression increases the formation of dimeric ATP synthase complexes and increases F₁F_o-ATP synthase activity. Thus, IF₁ regulates mitochondrial function and structure under both physiological and pathological conditions.