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Biomedical subjects

G Hauptmann

Publications and source records attributed to G Hauptmann.

At least 37 records · Page 2Linked to original sources
PubMed1997

Combined heterozygous deficiency of the classical complement pathway proteins C2 and C4.

Genetic deficiencies of components of the classical pathway of complement activation are associated with an increased risk for the development of autoimmune and immune complex-mediated diseases. In the present study we report on the molecular and clinical features associated with combined heterozygous C4 and C2 deficiency in 15 individuals investigated within six families. Approximately 30% of the individuals manifested SLE or another autoimmune condition. Heterozygous C2 deficiency was related to a 28-bp deletion in the C2 gene (C2 deficiency type I), in most cases within the HLA-A25 B18 C2Q0 BfS C4A4B2 DR2 haplotype. Among 13 partial C4-deficient haplotypes transmitted, 8 carried C4A*Q0 alleles and 5 C4B*Q0 alleles. In seven cases the C4A*Q0 alleles were associated with a deletion of the C4A/CYP21P genes within the HLA-B8 C2C BfS C4AQ0B1 DR3 haplotype. In three cases, the C4B*Q0 allele was associated with a deletion of the C4B/CYP21P genes within the HLA-B18 C2C BfF1 C4A3BQ0 DR3 haplotype. In the other cases, C4A*Q0 or C4B*Q0 was dependent on as yet uncharacterized defects in the C4 gene or in C4 gene expression. In view of the relatively high frequency of heterozygous C4 deficiency in the normal Caucasian population, the expected frequency of the combined deficiency should approximate 0.001.

Adult↗
PubMed1996

Class III POU genes of zebrafish are predominantly expressed in the central nervous system.

POU genes encode a family of transcription factors involved in a wide variety of cell fate decisions and in the regulation of differentiation pathways. We have searched for POU genes in the zebrafish, a popular model organism for the study of early development of vertebrates. Besides five putative pseudogenes we have identified five POU genes that are expressed during embryogenesis. Probes obtained by PCR were used to isolate full-length cDNAs. Four of the isolated genes encode proteins with class III POU domains. Analysis of genomic clones suggests that the fish genes in general do not contain introns, similar to class III genes of mammals. However, the C-termini of two of the encoded proteins vary due to facultative splicing of a short intervening sequence. These two genes show very strong similarities in their sequence. They have probably arisen by gene duplication, possibly as part of a larger scale duplication of part of the zebrafish genome. Analysis of the expression of the class III genes shows that they are predominantly expressed in the central nervous system and that they may play important roles in patterning the embryonic brain.

Amino Acid Sequence↗
PubMed1996

Allelic repertoire of the human MHC class I MICA gene.

The hallmark of the classical major histocompatibility complex (MHC) class I molecules is their astonishing level of polymorphism, a characteristic not shared by the nonclassical MHC class I genes. A distinct family of MHC class I genes has been recently identified within the human MHC class I region. The MICA (MHC class I chain-related A) gene in this family is a highly divergent member of the MHC class I family and has a unique pattern of tissue expression. We have sequenced exons encoding the extracellular alpha1, alpha2, and alpha3 domains of the MICA gene from twenty HLA homozygous typing cell lines and four unrelated individuals. We report the identification of eleven new alleles defined by a total of twenty-two amino acid substitutions. Thus, the total number of MICA alleles is sixteen. Interestingly, a tentative superimposition of MICA variable residues on the HLA-A2 structure reveals a unique pattern of distribution, concentrated primarily on the outer edge of the MICA putative antigen binding cleft, apparently bordering an invariant ligand binding site.

Alleles↗
PubMed1996

Complex expression of the zp-50 pou gene in the embryonic zebrafish brain is altered by overexpression of sonic hedgehog.

We report the characterization of the zebrafish zp-50 class III POU domain gene. This gene is first activated in the prospective diencephalon after the end of the gastrula period. During somitogenesis, zp-50 is expressed in a very dynamic and complex fashion in all major subdivisions of the central nervous system. After one day of development, zp-50 transcripts are present in the fore- and midbrain in several distinct cell clusters. In the hindbrain, zp-50 expression is found in two types of domains. Correct zp-50 expression in the ventral fore- and midbrain requires genes known to be involved in dorsoventral patterning of the zebrafish CNS. Transcripts of the sonic hedgehog (shh) gene encoding an intercellular signaling molecule are detected in the forming diencephalon shortly prior to the appearance of zp-50 mRNA. Correct expression in this region of both shh, and zp-50, requires a functional cyclops (cyc) locus: shh and zp-50 transcripts are likewise absent from the ventral rostral brain of mutant cyc-/- embryos. Injection of synthetic shh mRNA into fertilized eggs causes ectopic zp-50 expression at more dorsal positions of the embryonic brain. The close spatial and temporal coincidence of expression in the rostral brain, the similar response to the cyc- mutation, and the ectopic zp-50 expression in the injection experiments all suggest that zp-50 may directly respond to the reception of the Shh signal.

Amino Acid Sequence↗
PubMed1995

[Reconstruction of the diaphragm with various materials. An animal experiment study].

The relative merits of three methods of diaphragmatic hernia repair were evaluated in animals. Eighty Sprague-Dawley rats underwent laparotomy. The control group had an incision in the diaphragm with primary repair. The other three groups underwent partial resection of the left hemidiaphragm. The defects were repaired in 20 rats with lyophilized Dura, in 20 with polytetrafluoroethylene (PTFE) and in another 20 with absorbable serosa from a cow. Seventy-two animals survived the operation; they were followed up by electromyography (EMG) and post-mortem physical and histological examinations after 3 and 6 months. The EMG showed normal function for the absorbable material. Only scanty physiological waves were registered in the PTFE group. The examination for stretching and stress showed good results for all materials tested. The histological examinations amount to strong foreign body reactions with Dura and PTFE groups. The absorbable bovine serosa had vanished after 3 months postoperatively. It is concluded that bovine serosa can be recommended for diaphragmatic hernia.

Animals↗
PubMed1995

DNA methylation and the origin of complement factor B polymorphism.

BF is a polymorphic complement component encoded in the MHC. In each of two frequent alleles of BF, BF*FA and BF*FB, the difference in relation to the major allele BF*S has been shown to consist in the nonsynonymous substitution of only one base of the coding sequence. Both substitutions occur within the same codon and affect contiguous positions, corresponding to the dinucleotide CpG in BF*S. We propose here that BF*FA and BF*FB arose independently from BF*S by the frequently described transition mutations associated with cytosine methylation at CpG sites. By probing sperm DNA with methylation-sensitive restriction enzymes, we obtained experimental evidence of germ line methylation of the CpG site considered. The dinucleotide of the BF gene probably constitutes a site for recurrent mutation, and this is of relevance for the use of BF as a genetic marker, and the origin of forms of the protein with altered functional properties.

Base Sequence↗
PubMed1995

Pou-2--a zebrafish gene active during cleavage stages and in the early hindbrain.

We have cloned the zebrafish pou-2 gene which encodes a novel type (class VII) of POU domain. Maternal pou-2 transcripts are initially found in all blastomeres. However, during later cleavage stages pou-2 expression disappears in the marginal cells. Some of their progeny will form the first lineage restricted compartment during zebrafish development. Blastula pou-2 expression in confined exclusively to the deep embryonic layer (DEL) forming the embryo proper. No expression is found in extraembryonic tissues, i.e. the yolk syncytial layer (YSL) and the enveloping layer (EVL). Thus pou-2 expression during early embryogenesis correlates with the continuing absence of cell lineage restriction. Towards the end of gastrulation, pou-2 expression becomes confined to the neural plate, predominantly to the prospective hindbrain and to the spinal cord. pou-2 expression in the forming hindbrain is restricted to future rhombomeres r2 and r4. Retinoic acid treatment during epiboly alters the hindbrain domains of pou-2, suggesting that the entire anterior hindbrain acquires r4-like properties. This finding is supported by analysis of early pax-2 and krx-20 expression patterns in RA-treated zebrafish embryos. The changes resemble similar hindbrain transformations observed in other vertebrates, supporting an evolutionary conservation of the mechanisms segmenting the hindbrain of vertebrates. pou-2 appears to respond to the same signals as other presumed patterning genes. This observation, together with pou-2 expression in the hindbrain prior to morphological segmentation, suggests an important role for this putative transcription factor in establishing and specifying rhombomeric segments.

Animals↗
PubMed1995

[Changes in the polymorphism and concentrations of components of the class II complement after orthotopic transplantation of the liver].

OBJECTIVES AND METHODS: The genes of complement factor B, C2 and C4 are located within the major histocompatibility complex class III region on chromosome 6 in man. These components demonstrate a genetic polymorphism which, when determinated, can be used to define complotypes (association of C2, factor B, C4A and C4B allotypes). On the other hand the liver is the main source of the circulating complement component synthesis. The aim of this study was to analyse the kinetics of several complement component (C3, factor B and C4) concentrations in the plasma and to assess changes in the polymorphic pattern of the complotypes after orthotopic liver transplantation. Nephelometry was used for plasma level measurements and factor B, C2 and C4 typings were performed with high voltage electrophoresis or isofocalisation and immunofixation at intervals before, during and after orthotopic liver transplantation in eleven patients. RESULTS: Complotypes changes were observed 24 hours after liver transplantation in all patients. A slight decrease in C3, C4, and factor B plasma levels was observed in the first hours after transplantation. A rapid increase in the levels of these components was observed subsequently, with normalization in less than 15 days. CONCLUSION: These results demonstrate a rapid synthesis of complement components and the changes in complement polymorphic patterns after liver transplantation.

Adult↗
PubMed1994

Complete inherited deficiency of the fourth complement component in a child with systemic lupus erythematosus and his disease-free brother in a north African family.

Although null alleles of complement C4 genes (C4A*Q0 and C4B*Q0) are frequent in the normal population, the occurrence of two null alleles on the same chromosome is very rare and therefore complete C4 deficiency is exceptional. We describe a 16-year-old North African boy who presented with systemic lupus erythematosus with renal involvement and persistent undetectable classical pathway activity and C4 protein and hemolytic activity in plasma, with normal C3 levels. Similar complement abnormalities were observed in his healthy 12-year-old brother. Complete C4 deficiency was documented in the two brothers by investigation of the family and the lack of C4A and C4B bands upon phenotyping of C4. Southern blot analysis of the C4/CYP21 gene organization in the family indicated that the deficiency resulted from a deletion of the C4B/CYP21A genes associated with nonexpression of a C4A gene. The double-null haplotype was found to be associated with homozygous A2 B17 C2C BFF C4 AQ0 BQ0 DR7 HLA haplotype. Thus, similar C4 deficiencies with HLA identity may lead to different clinical presentations.

Adolescent↗
PubMed1994

Human factor B. Complete cDNA sequence of the BF*S allele.

The gene of human complement factor B (BF) is located within the class III region of the major histocompatibility complex. The knowledge of the coding sequence of the BF gene rests on a set of partial sequence studies reported by various sources, and full-length sequences ascribed to specific alleles of this polymorphic complement component have not yet been published. Now, we have isolated and sequenced a collection of cDNA clones derived from BF*S, the major BF allele. We present an uninterrupted, allele-specific sequence of the entire coding region and the 3' untranslated segment of the cDNA. Extensive comparison of this and previously available sequence data was carried out, and a number of base substitutions were observed in relation to some of the earlier sequences. The possibility that these differences arise from polymorphism in the BF gene is discussed.

Alleles↗
PubMed1994

Genomic analysis of the F subtypes of human complement factor B.

Factor B of human complement is encoded within the Major Histocompatibility Complex (MHC) and is polymorphic, with up to 30 alleles defined by electrophoretic mobility. One of the most common alleles, BF*F, is subdivided into the FA and FB subtypes, which differ at the gene level by non-synonymous base substitutions in the seventh codon. We have found at this position a new restriction site polymorphism, as a Bsl I site absent from the FB allele. Using this restriction polymorphism, we have developed a method for BF F subtype determination, based on amplification by polymerase chain reaction of the 5' end of the BF gene, and digestion with Bsl I. This new method has been applied to a panel of 29 selected BF F individuals. A single strand DNA conformation analysis of the same region of the gene allowed us to confirm the above DNA-based BF F subtyping. During this study, two BF*F1 alleles showed discrepancies between protein and DNA typing, which were confirmed by our sequencing data. These were identical, in the 5' region, to BF*S and BF*FB genes, respectively. In a comparison with two protein subtyping methods, identical results were found for only one third of the selected samples. The conflicting results may arise, in part, from previously undescribed molecular heterogeneity within BF F subtypes, or from the presence of a null allele. Our new method allows BF*F subtyping to be used with confidence in the definition of disease-associated MHC haplotypes.

Alleles↗
PubMed1993

Synthesis and regulation of complement components by human monocytes/macrophages and by acute monocytic leukemia.

Proteins of the complement system (C2, C3) are synthesized by human monocytes and macrophages, thus providing an important local source of these proteins in vivo which serve as a first-line host defense mechanism. In this study, we investigated the production of complement components C2, C4, and C9 by human monocytes/macrophages and by the pathologic cells of acute monocytic leukemia which represent a source of immature monocytic precursors. Human blood monocytes were collected and purified by cytapheresis and elutriation and leukemic cells by Ficoll gradient. Secretion of complement components was measured by a hemolytic assay. The evaluation of the mRNAs of the various complement components in the cells was performed by polymerase chain reaction (PCR) by adding 32P labeled deoxycytidinetriphosphate (dCTP) to the amplification step. Functional C2 was found to increase during in vitro maturation of macrophages up to the fourth week of culture. C2 mRNA was detected after amplification and increased during the maturation. Interferon-gamma (IFN-gamma) mediated a marked increase of the C2 mRNA. We found a decrease in synthesis of C4 mRNA during in vitro differentiation of human monocytes. The effect of IFN-gamma resulted in an increase in C4 mRNA. C9 mRNA was not detected although it was detected in the HepG2 hepatoma-derived cell line. Functional C2 was not detected by leukemic cells after 24 h of culture but little functional C4 was present in the cell supernatants. As they were by human monocytes and macrophages, C2 and C4 mRNAs were detected after amplification but C9 mRNAs were not detected.(ABSTRACT TRUNCATED AT 250 WORDS)

Actins↗
PubMed1992

Anti-(human LFA-1) monoclonal antibodies bind P815 murine tumour cells.

Using anti-CD11a and anti-CD18 monoclonal antibodies (mAbs) directed respectively against the alpha and the beta chains of LFA-1, we obtained an important and specific staining of P815 murine tumour cells. Both ascitic and cultured cells displayed a positive staining. Other murine tumours of haematopoietic origin, as well as lymphocytes or lymphoblasts from DBA/2 mice, were not labelled by the same monoclonal antibodies. These results were surprising since, to our knowledge, no case of cross-reaction between species has been reported with LFA-1. Moreover, competition assays showed that epitopes recognized by the two anti-CD11a antibodies were different from those identified by H35.89.9, a mAb raised against the murine LFA-1 alpha chain. Using allogeneic cytotoxic T lymphocytes, we also showed that anti-(human LFA-1) mAbs were unable to block the lysis of P815 by these effector cells. Thus, the putative functional properties of these structures, as well as their importance from an antigeneic point of view, remain to be assessed.

Animals↗
PubMed1992

[11th International Histocompatibility Workshop 1991: Personal data for the Multiple Sclerosis Study].

In our multiple sclerosis (MS) study as a part of the 11th IHWS we HLA-typed 6 MS families with 9 patients and defined the complement polymorphisms (BF, C2, C4) of these families. The aims of the study were the definition of the MS susceptibility gene and the investigation of the involvement of other factors in the etiopathogenesis of MS. The MS study of the IHWS demonstrated a strong association with HLA-DRw15 and -DWw6 in a Caucasian population. The heterozygous C2 deficiency in our family PD1 linked with the haplotype A25 B18 DR2 BFS C4A4 C4B2 confirmed by complement titration may express the participation of complement factors in the etiopathogenesis of MS resulting in immunogenetic heterogeneity of MS. Analysis of the 3 MS pairs of sisters shows the linkage of HLA with the assumed MS susceptibility gene. This could not be confirmed in the whole MS family study of the 11th IHWS.

Chromosome Mapping↗