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B Zabel

Publications and source records attributed to B Zabel.

At least 19 recordsLinked to original sources
PubMed1999

Mutations in the basic core promotor and the precore region of hepatitis B virus and their selection in children with fulminant and chronic hepatitis B.

The involvement of precore stop codon 1896-A and base exchanges in the AT-rich region at positions 1762 and 1764 of the hepatitis B core promotor has been controversely discussed in adults with fulminant hepatitis B. Because no data are currently available on children, we analyzed the basic core promotor (BCP) and precore region in children with chronic and fulminant hepatitis B. The BCP and precore region were sequenced directly and after cloning from mothers and infants. Thirteen children suffered from chronic liver disease, 6 of whom were treated with interferon alfa (IFN-alpha). All 13 patients seroconverted from hepatitis B e antigen (HBeAg) to hepatitis B e antigen antibodies (anti-HBe), and sera were analyzed before and after seroconversion. Nine vertically infected infants developed a fulminant course of hepatitis B. The occurrence of BCP (1762-T/1764-A, 7.7%) and precore (1896-A, 7.7%; 1899-A, 15%) mutations in chronic hepatitis B was rare. A genotype shift from D to A was observed in 3 patients after development of anti-HBe. A high number of base exchanges was detected in those infants with fulminant hepatitis B. Eight of nine showed a G-A exchange at positions 1896/97 (89%), 1899 (56%), and/or mutations at nucleotide (nt) positions 1762 (56%) and 1764 (78%). All virus strains belonged to genotype D, whereas in the only surviving infant, a D-to-A shift was detected. Hepatitis B virus (HBV) DNA clones were examined from 3 babies and 5 mothers. Our results showed a heterogeneous virus population in 4 of 5 mothers. In contrast, a homogeneous virus population emerged in the infants. According to our data, the analysis in children with fulminant and chronic hepatitis B revealed a striking presence of BCP and precore mutants in infants with fulminant hepatitis (FH) when compared with clinically inapparent anti-HBe-positive children (P <.002), which could be one factor in the pathogenesis of fulminant hepatitis B in children.

Acute Disease↗
PubMed1999

Regulation of chondrocyte differentiation by Cbfa1.

Cbfa1, a developmentally expressed transcription factor of the runt family, was recently shown to be essential for osteoblast differentiation. We have investigated the role of Cbfa1 in endochondral bone formation using Cbfa1-deficient mice. Histology and in situ hybridization with probes for indian hedgehog (Ihh), collagen type X and osteopontin performed at E13.5, E14.5 and E17.5 demonstrated a lack of hypertrophic chondrocytes in the anlagen of the humerus and the phalanges and a delayed onset of hypertrophy in radius/ulna in Cbfa1-/- mice. Detailed analysis of Cbfa1 expression using whole mount in situ hybridization and a lacZ reporter gene reveled strong expression not only in osteoblasts but also in pre-hypertrophic and hypertrophic chondrocytes. Our studies identify Cbfa1 as a major positive regulator of chondrocyte differentiation.

Animals↗
PubMed1999

The Wilms' tumor suppressor gene (wt1) product regulates Dax-1 gene expression during gonadal differentiation.

Gonadal differentiation is dependent upon a molecular cascade responsible for ovarian or testicular development from the bipotential gonadal ridge. Genetic analysis has implicated a number of gene products essential for this process, which include Sry, WT1, SF-1, and DAX-1. We have sought to better define the role of WT1 in this process by identifying downstream targets of WT1 during normal gonadal development. We have noticed that in the developing murine gonadal ridge, wt1 expression precedes expression of Dax-1, a nuclear receptor gene. We document here that the spatial distribution profiles of both proteins in the developing gonad overlap. We also demonstrate that WT1 can activate the Dax-1 promoter. Footprinting analysis, transient transfections, promoter mutagenesis, and mobility shift assays suggest that WT1 regulates Dax-1 via GC-rich binding sites found upstream of the Dax-1 TATA box. We show that two WT1-interacting proteins, the product of a Denys-Drash syndrome allele of wt1 and prostate apoptosis response-4 protein, inhibit WT1-mediated transactivation of Dax-1. In addition, we demonstrate that WT1 can activate the endogenous Dax-1 promoter. Our results indicate that the WT1-DAX-1 pathway is an early event in the process of mammalian sex determination.

Animals↗
PubMed1998

Heterozygous glycine substitution in the COL11A2 gene in the original patient with the Weissenbacher-Zweymüller syndrome demonstrates its identity with heterozygous OSMED (nonocular Stickler syndrome).

The original patient with the Weissenbacher-Zweymüller syndrome was analyzed for mutations in two candidate genes expressed in cartilage (COL2A1 and COL11A2). No mutations were found in the COL2A1 gene but the COL11A2 gene contained a single-base mutation that converted a codon for an obligate glycine to a codon for glutamate at position alpha 2-955 (G955E). The results here and those published previously indicate that the Weissenbacher-Zweymüller syndrome (heterozygous OSMED), nonocular Stickler syndrome, and homozygous OSMED are all caused by mutations in the COL11A2 gene.

Abnormalities, Multiple↗
PubMed1998

Ten novel mutations found in Aniridia.

Aniridia (AN) is a sight-threatening congenital ocular disorder characterized by iris hypoplasia, corneal pannus, foveal and optic nerve hypoplasia, cataract formation, and glaucoma. In two-thirds of the patients, AN is inherited in an autosomal dominant fashion with almost complete penetrance but variable expression. The remaining cases are sporadic. Aniridia has been shown to be associated with mutations in the PAX6 gene, located on chromosome 11p13, telomeric to the Wilms' tumor predisposition gene (WT1). This paper describes 14 mutations in the PAX6 gene in patients with AN. Among these 14 mutations, 10 have been unpublished until now. They result most probably in haploinsufficiency and consequently in a reduced protein level of functional PAX6 protein. The mutations reported here are scattered all over the gene, including the paired-box, the glycine-rich region, the homeobox, and the proline-serine-threonine (PST)-rich region.

Adolescent↗
PubMed1998

Cloning, characterization, and chromosomal assignment of the human ortholog of murine Zfp-37, a candidate gene for Nager syndrome.

In an effort to identify putative transcription factors involved in chondrocyte differentiation during human endochondral bone formation, a human fetal cartilage-specific cDNA library was screened with a degenerate oligonucleotide probe corresponding to a conserved stretch of eight amino acids from the zinc finger region of the Drosophila Krüppel gene family of DNA-binding proteins. Using this strategy, we have identified a novel zinc finger gene ZFP-37. ZFP-37 corresponds to a putative transcription factor containing 12 tandemly repeated zinc finger motifs and a Krüppel-associated box (KRAB) domain. The KRAB domain has been reported to function as a transcriptional repressor and is located in the amino terminus, while the zinc finger repeats are positioned at the carboxy-terminal end of ZFP-37. Gene mapping with a somatic cell hybrid panel and fluorescence in situ hybridization (FISH) localized ZFP-37 to human Chr 9q32. The gene is expressed at low level as a 3.2-kb mRNA in several tissues including fetal human cartilage. Sequence comparison revealed that ZFP-37 may represent the human homolog of the mouse gene Zfp-37. The map location and expression pattern suggest ZFP-37 as a candidate gene for a craniofacial-limb malformation, Nager syndrome (acrofacial dysostosis).

Amino Acid Sequence↗
PubMed1998

[Molecular genetic study of the PAX6 gene in aniridia patients].

INTRODUCTION: Aniridia represents a congenital ocular disorder with partial or complete iris hypoplasia. The disorder is associated with poor vision, glaucoma, corneal and lenticular opacities, ectopia lentis due to abnormal zonula fibers, as well as optic nerve and macular abnormalities. Aniridia may present as either hereditary or sporadic cases. Some of the sporadic cases develop Wilms' tumor, frequently as part of the WAGR syndrome (Wilms' tumor, aniridia, genitourinary abnormalities and mental retardation). PAX6, a candidate gene located on chromosome 11p13, is often mutated in aniridia patients. The gene encodes a transcription regulatory protein. METHOD: Analysis of the PAX6 gene was done using PCR (polymerase chain reaction), SSCP (single strand conformation polymorphism) and DNA sequencing. RESULTS: In 13 of 20 aniridia patients a PAX6 gene mutation was found. CONCLUSION: The mutations result in a gene product with reduced function or a reduced PAX6 protein level. Molecular analysis of aniridia is also a valuable diagnostic tool for Wilms' tumor risk evaluation, as patients with proven PAX6 mutations--in contrast to cases with large deletions of the 11p13 region--are at no increased risk to develop Wilms' tumor.

Aniridia↗
PubMed1998

Mutations in LMX1B cause abnormal skeletal patterning and renal dysplasia in nail patella syndrome.

The LIM-homeodomain protein Lmx1b plays a central role in dorso-ventral patterning of the vertebrate limb. Targeted disruption of Lmx1b results in skeletal defects including hypoplastic nails, absent patellae and a unique form of renal dysplasia (see accompanying manuscript by H. Chen et al.; ref. 2). These features are reminiscent of the dominantly inherited skeletal malformation nail patella syndrome (NPS). We show that LMX1B maps to the NPS locus and that three independent NPS patients carry de novo heterozygous mutations in this gene. Functional studies show that one of these mutations disrupts sequence-specific DNA binding, while the other two mutations result in premature termination of translation. These data demonstrate a unique role for LMX1B in renal development and in patterning of the skeletal system, and suggest that alteration of Lmx1b/LMX1B function in mice and humans results in similar phenotypes. Furthermore, we provide evidence for the first described mutations in a LIM-homeodomain protein which account for an inherited form of abnormal skeletal patterning and renal failure.

Amino Acid Sequence↗
PubMed1998

Acromesomelic dysplasia Maroteaux type maps to human chromosome 9.

Acromesomelic dysplasias are skeletal disorders that disproportionately affect the middle and distal segments of the appendicular skeleton. We report genetic mapping studies in four families with acromesomelic dysplasia Maroteaux type (AMDM), an autosomal recessive osteochondrodysplasia. A peak LOD score of 5.1 at recombination fraction 0 was obtained with fully informative markers on human chromosome 9. In three of the four families, the affected offspring are products of consanguineous marriages; if it is assumed that these affected offspring are homozygous by descent for the region containing the AMDM locus, a 6.9-cM AMDM candidate interval can be defined by markers D9S1853 and D9S1874. The mapping of the AMDM locus to human chromosome 9 indicates that AMDM is genetically distinct from the two other mapped acromesomelic dysplasias, Hunter-Thompson type and Grebe type, which are caused by mutations in CDMP1 on human chromosome 20.

Bone and Bones↗
PubMed1998

Mutation analysis of LMX1B gene in nail-patella syndrome patients.

Nail-patella syndrome (NPS), a pleiotropic disorder exhibiting autosomal dominant inheritance, has been studied for >100 years. Recent evidence shows that NPS is the result of mutations in the LIM-homeodomain gene LMX1B. To determine whether specific LMX1B mutations are associated with different aspects of the NPS phenotype, we screened a cohort of 41 NPS families for LMX1B mutations. A total of 25 mutations were identified in 37 families. The nature of the mutations supports the hypothesis that NPS is the result of haploinsufficiency for LMX1B. There was no evidence of correlation between aspects of the NPS phenotype and specific mutations.

Animals↗
PubMed1997

Loss of heterozygosity studies and deletion mapping identify two putative chromosome 14q tumor suppressor loci in renal oncocytomas.

Renal oncocytoma is considered to be a benign tumor that shares some phenotypic features with chromophobe renal cell carcinoma (RCC). Recently, we described high frequencies of allelic loss at 1p, 2p, 6p, 10p, 13q, 14q, 17p, and 21q, which correlate significantly with the chromophobe subtype of RCC. To investigate the genetic relationship between these two entities, we examined 12 oncocytomas for loss of heterozygosity (LOH) at these regions. In addition, we included markers for 3p, 5q, 7q, 11p, and 22q. The only chromosomal region showing similarly high frequencies of allelic loss for both subtypes was 14q. Therefore, a genetic relationship between renal oncocytoma and chromophobe RCC seems questionable. Eight of 12 oncocytomas (67%) showed LOH at 14q, a frequency that was significantly higher (P < 0.001, chi(2) test) than the frequencies of LOH in all other regions. To define regions potentially harboring novel tumor suppressor genes, we performed multifluorescence microsatellite analysis with 13 markers spanning 14q. Interstitial deletions at different regions of 14q were detected, with the highest frequencies at D14S258 (14q23-24.3) and D14S292 (14q32.1-32.2). 14q LOH might be associated with advanced-stage RCCs or other tumors, but it does not seem to indicate progression in oncocytomas. Its role in pathogenesis of renal oncocytomas remains to be clarified. Here, we provide evidence for two distinct tumor suppressor gene loci at 14q in renal oncocytoma, which will be useful for further fine-mapping studies of these critical regions.

Adenoma, Oxyphilic↗
PubMed1997

Functional characterization of human nucleosome assembly protein-2 (NAP1L4) suggests a role as a histone chaperone.

Histones are thought to play a key role in regulating gene expression at the level of DNA packaging. Recent evidence suggests that transcriptional activation requires competition of transcription factors with histones for binding to regulatory regions and that there may be several mechanisms by which this is achieved. We have characterized a human nucleosome assembly protein, NAP-2, previously identified by positional cloning at 11p15.5, a region implicated in several disease processes including Wilms tumor (WT) etiology. The deduced amino acid sequence of NAP-2 indicates that it encodes a protein with a potential nuclear localization motif and two clusters of highly acidic residues. Functional analysis of recombinant NAP-2 protein purified from Escherichia coli demonstrates that this protein can interact with both core and linker histones. We demonstrate that recombinant NAP-2 can transfer histones onto naked DNA templates. Deletion mutagenesis of NAP-2 demonstrates that both NH3- and COOH-terminal domains are required for histone transfer activity. Subcellular localization studies of NAP-2 indicate that it can shuttle between the cytoplasm and the nucleus, suggesting a role as a histone chaperone. Given the potential role of the human NAP-2 gene (HGMW-approved symbol NAP1L4) in WT etiology, we have elucidated the exon/intron structure of this gene and have analyzed the mutational status of NAP-2 in sporadic WTs. Our results, coupled with tumor suppression assays in G401 WT cells, do not support a role for NAP-2 in the etiology of WT. A putative role for NAP-2 in regulating cellular differentiation is discussed.

Amino Acid Sequence↗
PubMed1997

Kniest dysplasia: Dr. W. Kniest, his patient, the molecular defect.

Kniest dysplasia is a severe chondrodysplasia caused by the defective formation of type II collagen. We report about Dr. Kniest, who first described the condition in 1952, and his patient, who, at the age of 50 years is severely handicapped with short stature, restricted joint mobility, and blindness but is mentally alert and leads an active life. Molecular analysis of the patient's DNA showed a single base (G) deletion involving the GT dinucleotide at the start of intron 18 destroying a splice site of the COL2A1 gene. This is in accordance with molecular findings in other patients with Kniest dysplasia and confirms, in the original patient, that the disorder is caused by small inframe deletions often due to exon skipping as a result of COL2A1 splice site mutations.

Bone and Bones↗
PubMed1997

Human fibroblast growth factor receptor 3 gene (FGFR3): genomic sequence and primer set information for gene analysis.

We have determined the nucleotide sequence of the human fibroblast growth factor receptor 3 (FGFR3) gene, including 800 bp of the 5'-flanking region and compared the sequence with the previously published murine Fgfr3 gene. The organization of the gene is highly conserved between man and mouse. We used the intron sequences to design a set of primers that allow amplification of the 17 exons (2-18) that encode the complete open reading frame. Using these primers the FGFR3 gene can be amplified at the genomic level, which significantly facilitates mutational screening.

DNA Primers↗
PubMed1997

Resistance to thyroid hormone in a family caused by a new point mutation L330S in the thyroid receptor (TR) beta gene.

Resistance to thyroid hormone (RTH) is an inherited defect manifesting as variable tissue hyporesponsiveness to thyroid hormone, usually caused by mutations in the thyroid hormone receptor beta (TR beta) gene. Up to now 78 mutations in this gene have been identified, mostly clustered in two regions located in exon 9 and 10. We describe a new point mutation replacing the normal thymidine-1274 with a cytosine that results in the substitution of the normal leucine-330 with a serine (L330S) in the receptor protein. This mutation was identified in an 11-year-old boy who presented with symptoms and signs suggestive of both hyperthyroidism and hypothyroidism. Interestingly a mutation in the same codon (L330F) has been previously described in a patient who presented with stigmata suggestive of thyrotoxicosis.

Child↗
PubMed1996

A specific collagen type II gene (COL2A1) mutation presenting as spondyloperipheral dysplasia.

We report on a patient with a skeletal dysplasia characterized by short stature, spondylo-epiphyseal involvement, and brachydactyly E-like changes. This condition has been described as spondyloperipheral dysplasia and the few published cases suggest autosomal dominant inheritance with considerable clinical variability. We found our sporadic case to be due to a collagen type II defect resulting from a specific COL2A1 mutation. This mutation is the first to be located at the C-terminal outside the helical domain of COL2A1. A frameshift as consequence of a 5 bp duplication in exon 51 leads to a stop codon. The resulting truncated C-propeptide region seems to affect helix formation and produces changes of chondrocyte morphology, collagen type II fibril structure and cartilage matrix composition. Our case with its distinct phenotype adds another chondrodysplasia to the clinical spectrum of type II collagenopathies.

Amino Acid Sequence↗
PubMed1996

Osteopathia striata with cranial sclerosis: variable expressivity in a four generation pedigree.

Osteopathia striata is a manifestation of several bone dysplasias. In association with cranial sclerosis it represents a separate entity, which is not limited to the bones but may affect other structures, leading to abnormal face, cleft palate, deafness, heart defects, and vertebral anomalies. Neurological findings range from normal development to marked retardation with hydrocephalus, cranial nerve deficiencies and deafness. Ten families, including our own, clearly demonstrate autosomal dominant inheritance with female preponderance and great inter- and intrafamilial variability.

Abnormalities, Multiple↗