A unique RFLP in the human T-cell receptor gamma constant region gene TRGC1.
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Chromosome Mapping↗
Biomedical subjects
G Lefranc
Publications and source records attributed to G Lefranc.
Molecular mapping of the human T cell receptor gamma (TRG) genes and linkage of the variable and constant regions.
In the human T cell receptor gamma (TRG) locus, fourteen variable (TRGV) genes belonging to four subgroups have been identified upstream of two constant region (TRGC) genes. Three joining segments, JP1, JP and J1, have been localized upstream of TRGC1, and two others, JP2 and J2, upstream of TRGC2. In this report, we demonstrate that a unique Xho I fragment of 120 kilobases (kb) contains the fourteen TRGV genes and that the hybridization of that fragment in pulsed-field gel electrophoresis (PFGE) allows linkage of the variable region to the constant region locus. We also show that the variable and the constant regions are remarkably close to each other since the distance between V11, the most 3' V gamma gene, and JP1, the most 5' J gamma segment, is only 16 kb. With its 14 V gamma genes, spanning 100 kb, the two C gamma genes and 5 joining segments covering less than 40 kb and only 16 kb separating the most 3' V gene from the most 5' J segment, the human TRG locus spans 160 kb of genomic DNA and represents a particularly condensed locus compared to the other rearranging gene loci.
Amino Acid Sequence↗
BamHI and SacI RFLPs of the human immunoglobulin IGHG genes with reference to the Gm polymorphism in African people. Evidence for a major polymorphism.
In this paper, we extend the study of the IGHG gene RFLPs in black African persons and in some other individuals characterized by a Negroid admixture. We demonstrate a polymorphism that is much more important in black Africans, than in Caucasoids, mainly for the IGHG3 and G1 genes, the most 5' members of the IGHG multigene family. These genes encode for the IgG3 and IgG1 subclasses, which are of crucial biological importance.
Alleles↗
Molecular characterization of a ring chromosome 14 showing that the PI locus is centromeric to the D14S1 and IGH loci.
Molecular characterization of a ring chromosome 14 was carried out in a patient with the 46,XX,r(14) karyotype. The breakpoints shown by chromosome banding were within bands p11 and q32. Using molecular probes for the immunoglobulin heavy chain (IGH), D14S1 and PI loci located at 14q32, we showed that the IGH and D14S1 loci, located at 14q32.3 and 14q32.2 respectively, were deleted on the ring chromosome 14, but that the PI locus was not. Therefore, the chromosomal break lies between PI and D14S1. These results show that the order of these chromosome 14 markers is cen-PI-D14S1-IGH, in keeping with multipoint linkage data. Further molecular characterization of ring 14 chromosomes should lead to a detailed understanding of the molecular events and clinical consequences of the gene deletion associated with such chromosomal aberrations.
Blotting, Southern↗
Exon duplication and triplication in the human T-cell receptor gamma constant region genes and RFLP in French, Lebanese, Tunisian, and black African populations.
The human T-cell receptor gamma (TCRG) locus comprises 14 variable genes (TRGV), five joining segments (TRGJ), and two constant region genes (TRGC). The constant gamma 1 gene, TRGC1, consists of three exons, whereas the TRGC2 gene contains four or five exons due to the duplication or triplication of exon 2 and spans 9.5 kb or 12 kb, respectively. In this paper, we define the alleles of the T-cell receptor gamma J2 and C2 genes, and we show that two Hind III allelic fragments, 5.4 kb and 8 kb, characterize unambiguously the C2 gene with duplication or triplication of exon 2. We show also that the cDNA of the HPB-MLT cell line results from the transcription of an allelic TRGC2 gene with duplicated exon 2. We propose a model involving unequal crossing-overs to explain the organization and the evolution of the TRGC locus. Moreover, we analyze the TCRG haplotypes in four different populations (French, Lebanese, Tunisian, and Black African) to underline their interest for population genetics.
Alleles↗
A human immunoglobulin IGHG3 allele (Gmb0,b1,c3,c5,u) with an IGHG4 converted region and three hinge exons.
The five human IGHG genes consist of three constant domain exons plus one of or four hinge exon(s), the quadruplicated hinge region being characteristic of the IGHG3 gene. Besides this structural difference, the IGHG genes are polymorphic, as demonstrated by the restriction fragment length polymorphism and, at the protein level, by the Gm allotypic antigenic determinants. In this paper, we report the sequence of the G3m(b0, b1, c3, c5,u) IGHG3 allele, typical of the Black African populations and of populations with Negroid admixture, found in a homozygous Tunisian designated as LAT. We demonstrate that this G3 allele contains only three hinge exons instead of four (the probable result of an unequal crossing over) and that IGHG3 genes with triplicated hinge exons (and therefore encoding shorter gamma 3 chains) are present in healthy individuals from different populations. Moreover, we show that the LAT G3m (b0, b1, c3, c5, u) coding sequence results from the conversion, in the CH3 exon, of the G3m (b0, b1, b3, b4, b5, u, v) allele, the most frequent IGHG3 gene in the Negroid populations, by the homologous region of a IGHG4 gene. The structural features of the LAT IGHG3 allele, which are the lack of one hinge exon and its conversion by the IGHG4 gene, demonstrate that both crossing-over and gene conversion events occur in the evolution of the human IGHG genes.
Alleles↗
Deletion, insertion, and restriction site polymorphism of the T-cell receptor gamma variable locus in French, Lebanese, Tunisian, and black African populations.
The human T-cell receptor gamma region spans 160 kb of genomic DNA and is densely populated by coding sequences. Restriction fragment length polymorphisms have been previously documented for the constant region genes, the joining segments, and the variable genes belonging to subgroups I and IV. Here we further define the polymorphism of the V gamma I subgroup genes. based on complete mapping of the Eco RI and Taq I allelic restriction fragments. We describe seven haplotypes; five result from polymorphic restriction sites, the sixth corresponds to a deletion of about 10 kb encompassing V4 and V5, and the seventh results from an insertion of an additional gene, V3P, between V3 and V4. As a consequence of the deletion or insertion polymorphism, the number of V gamma I subgroup genes vary from seven in haplotype TRGVI*3 to ten in haplotype TRGVI*4, whereas the most common haplotype, TRGVI*1, has nine V genes, five of them being functional. Frequencies of the different TRGVI haplotypes in French, Lebanese, Tunisian, and Black African populations are given.
Black People↗
A multigene deletion in the human IGH constant region locus involves highly homologous hot spots of recombination.
A simultaneous absence of the IgG1, IgG2, IgG4, and IgA1 immunoglobulins (Ig) was unambiguously demonstrated in six healthy individuals of two different families (family HASS and family TOU). These individuals were shown to be homozygous for a large deletion in the immunoglobulin heavy chain constant region locus. This deletion, which encompasses the G1-EP1-A1-GP-G2-G4 genes, allowed us to predict an order for the IgCH genes and to localize GP between A1 and G2. In this paper, we study the deletion-recombination point in the IGH locus of individual EZZ from the TOU family. We show that the distance between the G3 and the E genes on the EZZ recombinant chromosome is 24.7 kb and that the multigene deletion in the IgCH locus involves two highly homologous regions (hsg3 and hsg4) which are hot spots of recombination, outside of the switch sequences.
Base Sequence↗
BstEII restriction fragment alleles and haplotypes of the human IGHG genes with reference to the BamHI/SacI RFLPs and to the Gm polymorphism.
In previous studies, we have described, for each of the five human immunoglobulin IGHG (C gamma) genes, BamHI, SacI and BamHI/SacI allelic restriction fragments. Further, we have determined BS (BamHI/SacI) linkage groups of alleles for the whole of the IGHG loci and we have demonstrated correlation with the Gm alleles and haplotypes. In this paper we characterize more precisely the polymorphism of the IGHG genes and, consequently, the structure and evolution of this multigene family, using the restriction enzyme BstEII and two different probes, a IGHG (C gamma) probe and a G3 (C gamma 3) specific probe. Alleles and haplotypes of the BstEII restriction fragments have been defined with reference to the BS alleles and haplotypes. New RFLPs of the IGHG genes are described and unambiguous correlations have been established with most of the Gm alleles and haplotypes. Thus, the IGHG gene RFLPs strengthen the Gm polymorphisms as powerful tools for the characterization of populations, disease and genetic marker linkage analyses, forensic medicine and evolution of these IGHG genes.
Alleles↗
No influence of conversions affecting allotype expression on the IgG subclass restriction of specific antibodies.
Antibodies against any given antigen are usually restricted to a particular class or subclass, a finding which has been suggested to be due to a preferential association between particular VH and CH genes. The DNA sequences regulating this process are as yet entirely unknown. It is likely however that some of these regulatory sequences are located within or in the immediate vicinity of the immunoglobulin genes themselves. We therefore analyzed the IgG subclass pattern of specific antibodies in sera from individuals displaying mutations, duplications, deletions or gene conversions event (replacing parts of the constant region genes of one subclass with that of another) affecting the allotype expression of immunoglobulin heavy chain constant region genes. Marked influences on antibody levels were noted in sera from individuals displaying duplication or deletions of constant region genes. However, in no case of gene conversion or mutation was there any measurable influence on the antibody pattern, clearly suggesting a lack of VH gene regulation by sequences within and possibly also immediately downstream of the constant region genes.
Antibody Specificity↗
A new TaqI polymorphism of the complement factor B gene.
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Chromosomes, Human, Pair 6↗
IgG subclass-associated affinity differences of specific antibodies in humans.
Human IgG subclasses differ in their biologic functions and are restricted as specific antibodies to certain Ag. The basis for this restriction is unknown but in order to characterize it further, we obtained serum preparations containing one single subclass by using subclass-specific mAb in affinity chromatography. Subsequently we determined the affinity of antibodies in the four IgG subclasses for gp30/p25, a hepatitis B surface Ag (HBsAg) complex, for a nine-amino acid cyclical peptide representing residues 139 to 147 of HBsAg, and for a peptide representing residues 126 to 140 of the hepatitis B virus pre-S2 region and the relative avidity of IgG1 and IgG2 antibodies for purified pneumococcal polysaccharide type 3. Affinities to the HBsAg showed a clear pattern of decreasing affinity in the order IgG1 greater than IgG2 greater than IgG3 greater than IgG4 both in sera from vaccinated and from naturally infected individuals. The relative avidities of antibodies to the polysaccharide Ag had a reverse pattern, IgG2 greater than IgG1. In individuals with or without Ig H chain gene deletions where the anti-HBsAg response was restricted to one subclass, the affinity was similar to that observed for the same subclass in sera from individuals who in addition possessed high or low affinity antibodies of other subclasses.
Adult↗
The human immunoglobulin pseudo-gamma IGHGP gene shows no major structural defect.
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Amino Acid Sequence↗
Definition of the RFLP alleles in the human immunoglobulin IGHG gene locus.
In order to define more precisely the polymorphism of the human immunoglobulin IGHG (C gamma) genes and, consequently, to understand the structure and evolution of this multigene family, we have investigated the Restriction Fragment Length Polymorphisms (RFLP) of the IGHG genes in 113 unrelated individuals and 18 families. Using the restriction enzymes Bam HI, Sac I and Eco RI, and hybridization to a IGHG probe and to a specific IGHG3 (C gamma 3) probe, we describe 47 different restriction fragments (RF) in the IGHG locus, allowing us to define at least 15 RFLP alleles for the different IGHG genes. Our data demonstrate that the restriction fragment length polymorphism is occasionally due to the presence or absence of a given restriction site as a consequence of a point mutation, such as the creation of an Eco RI site, at the codon 3 of exon 2 in one IGHG4 allele (IGHG4*D2). However, most of the RFLP we observed seem to result from the insertion or deletion of a few hundred base pairs as illustrated by the IGHG3 polymorphism.
Alleles↗
Restriction fragment haplotypes in the human immunoglobulin IGHG locus and their correlation with the Gm polymorphism.
Of the four human IgG subclass heavy chain (IGHG) genes, three--IGHG1, IGHG2 and IGHG3--have allelic forms which encode antigenic determinants called G1m, G2m and G3m allotypes for markers of the IgG1, IgG2 and IgG3 molecules. The alleles at these three closely linked loci are transmitted as Gm haplotypes, together with the IGHG4 and the IGHGP (or pseudo gamma) genes. Restriction Fragment Length Polymorphisms (RFLPs) have been described for all these IGHG genes, allowing us to define at least 15 RFLP alleles (N. Ghanem et al., Eur. J. Immunol. 1988. 18:1059). In this article, we determine unambiguously the Gm alleles and haplotypes and the associated RFLPs in French, Lebanese and Tunisian families, chosen for the various Gm phenotypes of their members, in order to correlate both these polymorphisms and to know the evolution of the IGHG multigene family. We were able to assign all the IGHG alleles to the Gm alleles and to their linked IGHG4 and IGHGP genes allowing us to define restriction fragment haplotypes of the IGHG gene family.
Alleles↗
Polymorphism of MHC class III genes: definition of restriction fragment linkage groups and evidence for frequent deletions and duplications.
The loci for the complement proteins BF and C2 and the two loci for C4 are closely linked to one another, as are the duplicated steroid 21 hydroxylase (21-OHase) genes to the C4A and C4B loci. The alleles of these four loci occur in specific combinations termed "complotypes". We have studied the gene frequencies of their different products in the Lebanese population and compared these values with those found in other populations. We observed a novel complotype (S B 4 6) in one family and a complotype with a so far undescribed variant of the C4A locus. Using several restriction fragment length polymorphisms (RFLPs), we have defined restriction fragment linkage groups. The combined use of C4 and 21-OHase probes allowed us to detect different types of deletions and duplications at these loci in the Lebanese population.
Chromosome Deletion↗
Ultrastructural identification of round-granule EC cells in rabbit fundic mucosa.
In endocrine (EC) cells of rabbit fundic mucosa, it is practically impossible to obtain unequivocal ultrastructural identification of all cells found in order to perform morphometric analysis. In addition to classic EC cells with pleomorphic granules, a cell type with entirely round granules is encountered which can be confused with non-EC cells. To solve this problem, all EC cells in our study were first identified by their 5-HT (immunocytochemistry) and argentaffinity. Examination of the fine structures of reactive cells then revealed that the round granules of EC cells were differentiated from those of non-EC cells by the existence of a dense core surrounded by a less dense halo, a feature providing unequivocal ultrastructural identification. EC cells with round granules showed less argentaffinity and less immunoreactivity to 5-HT as compared with classic EC cells. After labelling with [3H]L-dopa, EC cells with round-granules displayed an overall staining index higher than that of classic EC cells and comparable with that of D cells; however, the nuclear staining index was higher than that of D cells.
Animals↗
Polymorphism of immunoglobulin lambda constant region genes in populations from France, Lebanon and Tunisia.
Polymorphism of immunoglobulin lambda constant region (IGLC) genes has been studied in French, Lebanese and Tunisian people. The human IGLC polymorphisms appear as EcoRI restriction fragment length variations-8, 13, 18 or 23 kb-, these polymorphic fragments being related to a number of IGLC genes varying from six to nine per haploid genome. DNAs digested with the endonucleases EcoRI and HindIII were hybridized to a human IGLC probe and an immunoglobulin lambda intervening sequence region probe containing the J lambda 2 gene segment. Restriction fragments detected in Southern hybridizations were assigned to the IGLC locus map. Family studies allowed us to confirm the allelic nature of four of the different EcoRI restriction fragments observed. Frequencies of the corresponding alleles in French, Lebanese and Tunisian populations were determined and compared. The decrease of the 8-kb fragment (allele A1) frequency and, conversely, the increase of that of the 13-kb and 18-kb fragments (alleles A2 and A3) seemed to be correlated to a Negroid African contribution in the gene pool more important in Tunisia than in Lebanon.
Deoxyribonuclease EcoRI↗