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Biomedical subjects

O Bartsch

Publications and source records attributed to O Bartsch.

At least 19 recordsLinked to original sources
PubMed2001

Bioactivity of recombinant prorelaxin from the marmoset monkey.

The hormone relaxin (RLX) is generally present in the serum of humans and primates as a heterodimer, though some unprocessed prohormone may also be present. In order to test whether this proRLX is biologically relevant for human or primate physiology, recombinant marmoset monkey proRLX was synthesized in a baculovirus-infected cell system and tested in different bioassays. Marmoset proRLX is >70% identical to human H2 proRLX, especially in the so-called receptor-binding region of the B-peptide. The bioassay systems used were (a) cAMP production by human endometrial stromal cells and (b) cAMP production by the human monocyte cell line THP-1. In both bioassay systems recombinant proRLX showed comparable EC(50) values to pure porcine heterodimeric relaxin (porcine relaxin, 1.5-2.0 nM; marmoset prorelaxin 4.0-5.0 nM). Additionally, recombinant marmoset prorelaxin was shown to stimulate steroidogenesis in primary cultures of marmoset ovarian theca cells, though with a lower apparent activity than porcine relaxin. It thus appears that precursor processing of human or primate relaxin is not an essential prerequisite for the acquisition of bioactivity, as it is for the closely related hormone insulin, and that circulating prorelaxin is physiologically relevant.

Amino Acid Sequence↗
PubMed2001

Girl with phenotypic abnormalities and a de novo, apparently balanced translocation 46,XX,t(5;10)(q35.2q11.2).

We describe a three-year-old girl with a triangular face, epicanthus, midfacial hypoplasia, apparently low-set ears, a small mouth with thin vermilion border, and a small chin, hypermobile joints, developmental delay with insecure gait, dystonic movement disorder, speech defect, and a history of unexplained undernutrition. She has a de novo, apparently balanced translocation t(5;10)(q35.2;q11.2). Using fluorescence in situ hybridization (FISH), we located the breakpoints in the 1.5-Mb area defined by YAC 753f5 (5q35.2) and within the approximately 2-Mb interval between 10cen and YAC 933a3 (10q11.21).

Child, Preschool↗
PubMed2001

Characterization of relaxin binding in the uterus of the marmoset monkey.

The ovarian peptide hormone relaxin (RLX) plays an important role in the regulation of the endometrium both during the cycle and in early pregnancy. RLX interacts with specific receptors on endometrial stromal cells causing these to decidualize. In order to characterize the molecules with which RLX interacts in the primate uterus, a methodology based on a fully bioactive preparation of biotinylated porcine RLX was applied to cryosections of the uterus of female marmoset monkeys. Specific RLX binding was weakly detected in the proliferative phase in isolated endometrial stromal cells. In the secretory phase, the positively reacting cells increased in staining intensity and in number and also included some epithelial cells. Further increases occurred in pregnancy, but RLX binding in the endometrium decreased at the end of the cycle if pregnancy did not occur. The myometrium showed weak staining which did not vary through the cycle, but increased in pregnancy. Electrophoretic analysis of the RLX-binding moieties in these tissue sections indicated that a protein of approximately 40 kDa was the principal RLX-binding molecule, while minor specific bands were detectable at approximately 100 and approximately 200 kDa. The binding of biotinylated RLX could be specifically suppressed by co-incubation with unlabelled RLX, but not by insulin, IGF-I or biotin. This technique therefore allows the detection and molecular characterization of specific RLX binding in the primate uterus. In the marmoset monkey, the pattern of specific binding closely reflects the RLX-dependent physiology during implantation and early pregnancy, implying the probable involvement of a specific RLX receptor.

Animals↗
PubMed2001

Relaxin signalling links tyrosine phosphorylation to phosphodiesterase and adenylyl cyclase activity.

The relaxin receptor has so far avoided molecular cloning and characterization. We have therefore characterized the signalling events activated by relaxin (RLX), using two different cell culture-based bioassay systems: primary human endometrial stromal cells from the cycle (ESC) and the human monocyte cell line THP-1. Upon RLX stimulation, both cell types showed a rapid increase in cAMP accumulation, which could be inhibited by an inhibitor of G-protein activation, GDP-beta-S. However, evolutionarily one would expect the RLX receptor, like those for the structurally related hormones insulin and insulin-like growth factor-I, to involve tyrosine kinase activity. The specific tyrphostins AG 1478, AG 527 and AG 879 inhibited the RLX-stimulated cAMP response in human ESC and THP-1 cells in a dose-dependent manner, though the potent broad range tyrphostin AG 213 had no effect. Also, treatment of THP-1 cells with the potent phosphotyrosine phosphatase inhibitors bpV(phen) and mpV(pic) increased RLX-stimulated cAMP accumulation in a dose-dependent manner. The effect of the general tyrosine kinase inhibitor genistein (which can also inhibit some phosphodiesterases) on RLX-mediated cAMP accumulation strongly depended on the activity status of phosphodiesterase. In the absence of a phosphodiesterase inhibitor, genistein enhanced RLX-stimulated cAMP accumulation in both bioassays. When phosphodiesterase was inhibited by isobutylmethylxanthine, this effect was not observed. The results imply that activation of the RLX receptor uses tyrosine kinase signalling to control phosphodiesterase activity, and hence to up-regulate intracellular cAMP.

Adenylyl Cyclases↗
PubMed2001

[Analysis of a case of balanced chromosome translocation and phenotypic abnormality by fluorescence in situ hybridization].

OBJECTIVE: To delineate the chromosome structural aberration in a case of chromosome translocation by fluorescence in situ hybridization(FISH) technique and precisely identify the breakpoints. METHODS: The whole chromosome point 5(wcp5) and locus- specific probes derived from yeast artificial chromosomes(YACs) mapping the nearby region of breakpoints were used to delineate the translocation t(5;10) found by high resolution G-banding examination in a case with congenital abnormality. RESULTS: A balanced translocation was confirmed and the breakpoints were located in the 1.5 Mb area on chromosome 5 and within the approximately 3 Mb interval on chromosome 10. CONCLUSION: The phenotypic abnormality might result from the disruption of disease-associated gene(s) or microrearrangement(s) on the site of breakpoint(s).

Child, Preschool↗
PubMed2000

Penoscrotal inversion, hypospadias, imperforate anus, facial anomalies, and developmental delay: definition of a new clinical syndrome.

We describe a 2-month-old boy with penoscrotal inversion, hypospadias, imperforate anus, facial anomalies, developmental retardation, and a subtelomeric deletion of chromosome 13q. His phenotype with anogenital malformations and characteristic facies closely resembled two unrelated patients with minute deletions of chromosome 13q who we reported earlier. In addition, he had unilateral renal agenesis. We propose that these patients represent a clinically recognizable, novel chromosomal microdeletion syndrome. The findings indicate the presence of a major gene(s) on chromosome 13q33.2qter that regulate(s) the migration and development of ano-reno-genital cells and organs. We speculate that mutations of this developmental gene(s) may also result in more frequent congenital malformations (isolated hypospadias, uterus bicornis, unilateral renal agenesis). Additional studies are needed to further delineate the genetic defect.

Abnormalities, Multiple↗
PubMed1999

Identification of cyclin A/Cdk2 phosphorylation sites in B-Myb.

B-myb is a highly conserved member of the myb proto-oncogene family that encodes a ubiquitously expressed 110-kDa sequence-specific DNA-binding protein. Transactivation of Myb-inducible promoters by B-Myb is repressed by a regulatory domain located at the C-terminus of the protein. Cyclin A/Cdk2-mediated phosphorylation apparently releases the negative constraint and triggers B-Myb transactivation potential. Two-dimensional tryptic phosphopeptide analysis indicated that the majority of the sites phosphorylated in vivo are targeted in vitro by cyclin A/Cdk2. Six sites in B-Myb fulfil the requirements for recognition by Cdk2. Using point mutation of the phosphorylation sites to nonphosphorylatable amino acids, we show that five of these sites are targets for Cdk2 in vivo. Mutation of one of these residues (T524) to alanine diminished the ability of B-Myb to promote transcription of a reporter gene, suggesting that phosphorylation of B-Myb at this site is important for the regulation of its activity by cyclin A/Cdk2.

Amino Acid Substitution↗
PubMed1999

The novel contiguous gene syndrome of myotubular myopathy (MTM1), male hypogenitalism and deletion in Xq28:report of the first familial case.

Hu et al. (1996) and Laporte et al. (1997) recently proposed a novel contiguous gene syndrome of myotubular myopathy, abnormal male genital development and deletion in Xq28. We studied a family where two male infants, both deceased, had myotubular myopathy and intersexual genitalia. Using FISH we detected in the mother a hemizygous deletion including the myotubularin gene MTM1 and F18 (a gene of yet unknown function). DNA studies with STR-markers (short tandem repeats) within and flanking the deleted segment confirmed the deletion in the family and were used for prenatal diagnosis. Our findings confirm the existence of this novel contiguous gene syndrome and support that the deletion of the F18 gene, or a neighboring gene, may cause ambiguous genitalia or severe hypospadias in males. The mother had low muscle power and marked menstrual irregularities which may indicate that she is a manifesting carrier and that the deletion may include a gene (F18 or other) for gonadal function in females.

Adult↗
PubMed1998

Familial Williams-Beuren syndrome.

Williams-Beuren syndrome (WBS) occurs sporadically; however, at least four familial cases of WBS have been described previously. We describe a mother and her son with typical WBS. The diagnosis of WBS in the son was confirmed by molecular cytogenetic analysis fluorescence in situ hybridization. He had a deletion of 7q11.23 at the ELN locus. The mother was diagnosed after the identification of WBS in her affected son. She is deceased and was thus not studied by FISH. However, her combined symptoms make it very clear that she had WBS. Two traits uncommon in WBS were observed, unilateral renal hypoplasia in the mother and a hemivertebra at L5 in the son.

Adult↗
PubMed1998

Deletion mapping by FISH with BACs in patients with partial monosomy 22q13.

Patients with deletions in 22q13 are known to have phenotypic features that include normal or accelerated growth, large hands and feet, hypotonia, delayed psychomotor development and mild facial dysmorphism. To date, very few cases have been investigated by detailed molecular genetic analysis. We have analyzed three new patients with terminal deletions in 22q. We compared the cytogenetic observations with molecular data assessed by fluorescence in situ hybridization and an array of characterized bacterial artificial chromosome recombinants. The shortest region of deletion overlap is localized in 22q13.2-qter distal to the marker D22S94, but the telomeric repeat in the deleted chromosome appears to remain intact. When parental alleles were investigated in two of the three patients, the aberrant homolog was found to be of paternal origin in both cases. Although the deleted region still spans >20 cM, molecular analysis of additional patients and screening for new genes might help in elucidating candidate genes connected with the dysmorphisms defined by deletions of 22q13.

Child, Preschool↗
PubMed1997

A small deletion of 16q23.1-->16q24.2 [del(16)(q23.1q24.2).ish del(16)(q23.1q24.2)(D16S395+, D16S348-, P5432+)] in a boy with iris coloboma and minor anomalies.

We report on a 5-year-old boy with bilateral coloboma of iris, short stature, moderate developmental delay, and a few minor craniofacial anomalies. High-resolution GTG banding showed a small distal deletion of one chromosome 16 [del(16)(q23.1q24.2)]. Molecular refinement of the deletion breakpoints yielded that the proximal breakpoint at 16q23.1 is located between loci D16S395 (present) and D16S348 (absent). Comparison with previously published cases of deletion 16q demonstrated that the clinical phenotype is not a recognizable 16q- syndrome and different from the two cases of deletions of 16(q22.1 to q24.1) described by Callen et al. [1993]. Evidently, deletion 16(q23.1q24.2) has a milder phenotypic effect than other interstitial and distal 16q deletions.

Child, Preschool↗
PubMed1997

Phosphorylation and activation of B-Myb by cyclin A-Cdk2.

BACKGROUND: Cyclins and their catalytic partners, the cyclin-dependent kinases (Cdks), function as key regulators of the eukaryotic cell cycle. Specific cyclin-Cdk complexes are active at successive stages during the cell cycle and control cell-cycle progression by phosphorylating specific target proteins, most of which have not yet been identified. B-Myb, a conserved member of the Myb oncoprotein family, is a sequence-specific DNA-binding protein expressed in virtually all proliferating mammalian cells. Increasing evidence suggests that B-Myb plays an important role during the late G1 and early S phases of the cell cycle. In this study, we have examined the regulation of B-Myb activity by cyclin-Cdks. RESULTS: We found that the transcriptional transactivation potential of B-Myb was repressed by a regulatory domain located at the carboxyl terminus of the protein. Coexpression of B-Myb and cyclin A relieved this repression by phosphorylation of B-Myb in its carboxy-terminal region. Tryptic phosphopeptide mapping revealed that endogenous B-Myb was phosphorylated in cells undergoing S phase. CONCLUSIONS: This work provides evidence for a link between the Myb oncoprotein family and the cell-cycle machinery. We have shown that the carboxyl terminus of B-Myb acts as a cell-cycle sensor that regulates the transactivation function of B-Myb. Moreover, our studies have identified B-Myb as a target of cyclin A-Cdk2 and have indicated that B-Myb activity is regulated by phosphorylation mediated by cyclin A-Cdk2.

3T3 Cells↗