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A Winterpacht

Publications and source records attributed to A Winterpacht.

At least 19 recordsLinked to original sources
PubMed2001

Regulation of glomerular basement membrane collagen expression by LMX1B contributes to renal disease in nail patella syndrome.

Basement membrane (BM) morphogenesis is critical for normal kidney function. Heterotrimeric type IV collagen, composed of different combinations of six alpha-chains (1-6), is a major matrix component of all BMs (ref. 2). Unlike in other BMs, glomerular BM (GBM) contains primarily the alpha 3(IV) and alpha 4(IV) chains, together with the alpha 5(IV) chain. A poorly understood, coordinated temporal and spatial switch in gene expression from ubiquitously expressed alpha 1(IV) and alpha 2(IV) collagen to the alpha 3(IV), alpha 4(IV) and alpha 5(IV) chains occurs during normal embryogenesis of GBM (ref. 4). Structural abnormalities of type IV collagen have been associated with diverse biological processes including defects in molecular filtration in Alport syndrome, cell differentiation in hereditary leiomyomatosis, and autoimmunity in Goodpasture syndrome; however, the transcriptional and developmental regulation of type IV collagen expression is unknown. Nail patella syndrome (NPS) is caused by mutations in LMX1B, encoding a LIM homeodomain transcription factor. Some patients have nephrosis-associated renal disease characterized by typical ultrastructural abnormalities of GBM (refs. 8,9). In Lmx1b(-/-) mice, expression of both alpha(3)IV and alpha(4)IV collagen is strongly diminished in GBM, whereas that of alpha1, alpha2 and alpha5(IV) collagen is unchanged. Moreover, LMX1B binds specifically to a putative enhancer sequence in intron 1 of both mouse and human COL4A4 and upregulates reporter constructs containing this enhancer-like sequence. These data indicate that LMX1B directly regulates the coordinated expression of alpha 3(IV) and alpha 4(IV) collagen required for normal GBM morphogenesis and that its dysregulation in GBM contributes to the renal pathology and nephrosis in NPS.

Animals↗
PubMed2000

Mtr1, a novel biallelically expressed gene in the center of the mouse distal chromosome 7 imprinting cluster, is a member of the Trp gene family.

We recently described a novel putative Ca(2+) channel gene, MTR1, which shows a high level of homology to the human TRPC7 gene and the melastatin 1 (MLSN1) gene, another Trp (transient receptor potential protein)-related gene whose transcript was found to be downregulated in metastatic melanomas. It maps to human chromosome band 11p15.5, which is associated with the Beckwith-Wiedemann syndrome and predisposition to a variety of neoplasias. Here we report the isolation and characterization of the murine orthologue Mtr1. The chromosomal localization on distal chromosome 7 places it in a cluster of imprinted genes, flanked by the previously described Tapa1 and Kcnq1 genes. The Mtr1 gene encodes a 4.4-kb transcript, present in a variety of fetal and adult tissues. The putative open reading frame consists of 24 exons, encoding 1158 amino acids. Transmembrane prediction algorithms indicate the presence of six membrane-spanning domains in the proposed protein. Imprinting analysis, using RT-PCR on RNA from reciprocal mouse crosses harboring a sequence polymorphism, revealed biallelic expression of Mtr1 transcripts at all stages and tissues examined.

Alleles↗
PubMed2000

LMX1B transactivation and expression in nail-patella syndrome.

Lmx1b, a member of the LIM homeodomain protein family, is essential for the specification of dorsal limb fates at the zeugopodal and autopodal level in vertebrates. We and others have shown that a skeletal dysplasia, nail-patella syndrome (NPS), results from mutations in LMX1B. While it is a unique mesenchymal determinant of dorsal limb patterning during vertebrate development, the mechanism by which LMX1B mutations generate the NPS phenotype has not been addressed at a transcriptional level or correlated with its spatial pattern of gene expression. In this study, in situ hybridizations of Lmx1b on murine limb sections reveal strong expression in dorsal mesenchymal tissues (precursors of muscle, tendons, joints and patella) and, interestingly, also in anterior structures of the limb, explaining the anterior to posterior gradient of joint and nail dysplasia observed in NPS patients. Transfection studies showed that both the LIM domain-interacting protein, LDB1, and the helix-loop-helix protein, E47/shPan1, can regulate LMX1B action. While co--transfections of E47/shPan1 with LMX1B result in a synergistic effect on reporter activity, LDB1 down-regulated LMX1B-mediated transactivation irrespective of E47/shPan1. Mutant LMX1B proteins containing human mutations affecting each of the helices or the N-terminal arm of the homeodomain abolished transactivation, while LIM B and truncation mutations retained residual activity. These mutations fail to act in a dominant-negative manner on wild-type LMX1B in mixing studies, thereby supporting haploinsufficiency as the mechanism underlying NPS pathogenesis.

Animals↗
PubMed2000

A novel mutation in FGFR-3 disrupts a putative N-glycosylation site and results in hypochondroplasia.

Fibroblast growth factor receptor 3 (FGFR3) is a glycoprotein that belongs to the family of tyrosine kinase receptors. Specific mutations in the FGFR3 gene are associated with autosomal dominant human skeletal disorders such as hypochondroplasia, achondroplasia, and thanatophoric dysplasia. Hypochondroplasia (HCH), the mildest form of this group of short-limbed dwarfism disorders, results in approximately 60% of cases from a mutation in the intracellular FGFR3-tyrosine kinase domain. The remaining cases may either be caused by defects in other FGFR gene regions or other yet unidentified genes. We describe a novel HCH mutation, the first found outside the common mutation hot spot of this condition. This point mutation, an N328I exchange in the extracellular Ig domain III of the receptor, seems to be unique as it affects a putative N-glycosylation site that is conserved between different FGFRs and species. The amino acid exchange itself most probably has no impact on the three-dimensional structure of the receptor domain, suggesting that the phenotype is the result of altered receptor glycosylation and its pathophysiological consequences.

Amino Acid Substitution↗
PubMed2000

Identification and characterization of MTR1, a novel gene with homology to melastatin (MLSN1) and the trp gene family located in the BWS-WT2 critical region on chromosome 11p15.5 and showing allele-specific expression.

Alterations within human chromosomal region 11p15.5 are associated with the Beckwith-Wiedemann syndrome (BWS) and predisposition to a variety of neoplasias, including Wilms' tumors (WTs), rhabdoid tumors and rhabdomyosarcomas. To identify candidate genes for 11p15. 5-related diseases we compared human genomic sequence with expressed sequence tag and protein databases from different organisms to discover evolutionarily conserved sequences. Herein we describe the identification and characterization of a novel human transcript related to a putative Caenorhabditis elegans protein and the trp (transient receptor potential) gene. The highest homologies are observed with the human TRPC7 and with melastatin 1 ( MLSN1 ), whose transcript is downregulated in metastatic melanomas. Other genes related to and interacting with the trp family include the Grc gene, which codes for a growth factor-regulated channel protein, and PKD1/PKD2, involved in polycystic kidney disease. The novel gene presented here (named MTR1 for MLSN1 - and TRP -related gene 1) resides between TSSC4 and KvLQT1. MTR1 is expressed as a 4.5 kb transcript in a variety of fetal and adult tissues. The putative open reading frame is encoded in 24 exons, one of which is alternatively spliced leading to two possible proteins of 872 or 1165 amino acids with several predicted membrane-spanning domains in both versions. MTR1 transcripts are present in a large proportion of WTs and rhabdomyosarcomas. RT-PCR analysis of somatic cell hybrids harboring a single human chromosome 11 demonstrated exclusive expression of MTR1 in cell lines carrying a paternal chromosome 11, indicating allele-specific inactivation of the maternal copy by genomic imprinting.

Adult↗
PubMed1999

Isolation, characterization, and mapping of a zinc finger gene, ZFP95, containing both a SCAN box and an alternatively spliced KRAB A domain.

A new zinc finger gene of the Krüppel family was identified by screening a human fetal cartilage cDNA library with degenerate oligonucleotides. Sequence analysis indicates that ZFP95 contains 12 highly conserved zinc finger motifs at the C-terminus and a SCAN box as well as a KRAB A domain at the N-terminus of the protein. ZFP95 represents a member of a new subclass of Krüppel zinc finger proteins containing both a SCAN box and a KRAB domain. Sequence comparison revealed that ZFP95 is the human ortholog of murine Zfp95, which is differentially expressed during spermatogenesis. We demonstrate that ZFP95 is ubiquitously expressed in adult and fetal tissues with the strongest expression in testis. Two transcripts, 4. 2 and 4.6 kb, were detected in all tissues tested. In testis, a third transcript of 3.8 kb was present. RT-PCR analysis confirmed alternative splicing for the KRAB A domain and an upstream exon leading to three transcripts of ZFP95 with and without this transcriptional repressor domain. Finally, we show that ZFP95 maps on human chromosome 7q22 between the markers D7S651 and WI-5853.

Adult↗
PubMed1999

LETM1, a novel gene encoding a putative EF-hand Ca(2+)-binding protein, flanks the Wolf-Hirschhorn syndrome (WHS) critical region and is deleted in most WHS patients.

Deletions within human chromosome 4p16.3 cause Wolf-Hirschhorn syndrome (WHS), which is characterized by severe mental and developmental defects. It is thought that haploinsufficiency of more than one gene contributes to the complex phenotype. We have cloned and characterized a novel gene (LETM1) that is deleted in nearly all WHS patients. LETM1 encodes a putative member of the EF-hand family of Ca(2+)-binding proteins. The protein contains two EF-hands, a transmembrane domain, a leucine zipper, and several coiled-coil domains. On the basis of its possible Ca(2+)-binding property and involvement in Ca(2+) signaling and/or homeostasis, we propose that haploinsufficiency of LETM1 may contribute to the neuromuscular features of WHS patients.

Amino Acid Sequence↗
PubMed1999

Retraction.

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Retraction Notice↗
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

The centromeric/nucleolar chromatin protein ZFP-37 may function to specify neuronal nuclear domains.

Murine ZFP-37 is a member of the large family of C2H2 type zinc finger proteins. It is characterized by a truncated NH2-terminal Krüppel-associated box and is thought to play a role in transcriptional regulation. During development Zfp-37 mRNA is most abundant in the developing central nervous system, and in the adult mouse expression is restricted largely to testis and brain. Here we show that at the protein level ZFP-37 is detected readily in neurons of the adult central nervous system but hardly in testis. In brain ZFP-37 is associated with nucleoli and appears to contact heterochromatin. Mouse and human ZFP-37 have a basic histone H1-like linker domain, located between KRAB and zinc finger regions, which binds double-stranded DNA. Thus we suggest that ZFP-37 is a structural protein of the neuronal nucleus which plays a role in the maintenance of specialized chromatin domains.

Amino Acid Sequence↗
PubMed1998

Divergently transcribed overlapping genes expressed in liver and kidney and located in the 11p15.5 imprinted domain.

Human chromosomal band 11p15.5 has been shown to contain genes involved in the development of several pediatric and adult tumors and in Beckwith-Wiedemann syndrome (BWS). Overlapping P1 artificial chromosome clones from this region have been used as templates for genomic sequencing in an effort to identify candidate genes for these disorders. PowerBLAST identified several matches with expressed sequence tags (ESTs) from fetal brain and liver cDNA libraries. Northern blot analysis indicated that two of the genes identified by these ESTs encode transcripts of 1-1.5 kb with predominant expression in fetal and adult liver and kidney. With RT-PCR and RACE, full-length transcripts were isolated for these two genes, with the largest open reading frames encoding putative proteins of 253 and 424 amino acids. Database comparison of the predicted amino acid sequence of the larger transcript indicated homology to integral membrane organic cation transporters; hence, we designate this gene ORCTL2 (organic cation transporter-like 2). An expressed sequence polymorphism provided evidence that the ORCTL2 gene exhibits "leaky" imprinting in both human fetal kidney and human fetal liver. The mouse orthologue (Orctl2) was identified, and a similar polymorphism was used to demonstrate maternal-specific expression of this gene in fetal liver from interspecific F1 mice. The predicted protein of the smaller gene showed no significant similarity in the database. Northern and RACE analyses suggest that this gene may have multiple transcription start sites. Determination of the genomic structure in humans indicated that the 5'-end of this transcript overlaps in divergent orientation with the first two exons of ORCTL2, suggesting a possible role for antisense regulation of one gene by the other. We, therefore, provisionally name this second transcript ORCTL2S (ORCTL2-antisense). The expression patterns of these genes and the imprinted expression of ORCTL2 are suggestive of a possible role in the development of Wilms tumor (WT) and hepatoblastoma. Although SSCP analysis of 62 WT samples and 10 BWS patients did not result in the identification of any mutations in ORCTL2 or ORCTL2S, it will be important to examine their expression pattern in tumors and BWS patients, since epigenetic alteration at these loci may play a role in the etiology of these diseases.

Amino Acid Sequence↗
PubMed1998

Cloning and characterization of a novel gene (TM7SF1) encoding a putative seven-pass transmembrane protein that is upregulated during kidney development.

We have used the cDNA differential display of mRNA technique to isolate genes differentially regulated during kidney development. Here we report the identification of a novel gene, TM7SF1, which is upregulated in the course of kidney development. The full-length cDNA of TM7SF1 is about 2.4 kb and contains an open reading frame of 1197 nucleotides. The predicted secondary structure of the corresponding protein displays seven putative helical transmembrane domains, a structural feature shared by all members of the G-protein-coupled receptor class of transmembrane proteins. Two minor alternatively spliced versions of approximately 2.3 and approximately 2.2 kb could be detected, one of which contains a nearly identical open reading frame with a truncated carboxy-terminus of the deduced protein. The second alternatively spliced version harbors a completely shifted open reading frame with a potential new ATG start codon. By the use of single-chromosome hybrid cells and fluorescence in situ hybridization experiments, TM7SF1 could be localized to chromosome 1q42-q43. Human multiple tissue Northern blot analysis revealed TM7SF1 transcripts in human kidney, heart, brain, and placenta tissue. Studies on Wilms tumor samples showed variable TM7SF1 expression, ranging from nearly undetectable levels to an abundant level of expression comparable to that of adult kidney tissue.

Adult↗
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

Novel WT1 mutation, 11p LOH, and t(7;12) (p22;q22) chromosomal translocation identified in a Wilms' tumor case.

About 5-10% of sporadic Wilms' tumors (WT) are associated with mutations in the Wilms' tumor 1 gene (WT1). More than 90% of patients with Denys-Drash syndrome (DDS; characterized by renal nephropathy, gonadal anomaly, and predisposition to WT) show constitutional intragenic WT1 mutations. We describe a novel WT1 stop-mutation in exon 2. This heterozygous germline mutation was detected in a one-year-old girl who was bilaterally affected with Wilms' tumor but without any other clinical manifestations of DDS. The C-to-A transversion is predicted to result in a polypeptide comprising only the first 165 amino acids of the WT1 protein. Loss of heterozygosity (LOH) studies comparing tumor DNA with lymphocyte DNA revealed LOH for the entire short arm of chromosome 11 in tumor tissue. In addition to the chromosome 11 lesions, the tumor showed a seemingly balanced chromosomal translocation t(7;12) (p22;q22) as the only visible cytogenetic aberration.

Chromosomes, Human, Pair 11↗
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

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

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↗