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C M Disteche

Publications and source records attributed to C M Disteche.

At least 19 recordsLinked to original sources
PubMed2003

Multiple fetal anomalies associated with subtle subtelomeric chromosomal rearrangements.

We report two cases of multiple fetal anomalies detected by prenatal ultrasound and associated with subtle subtelomeric chromosomal rearrangements. The first case presented at 25 weeks of gestation with an enlarged cisterna magna and ventriculomegaly. Karyotyping of amniocytes showed a subtle terminal abnormality of chromosome 6q. Thereafter, screening of all unique chromosomal subtelomeric regions using a panel of telomere-specific, fluorescence in situ hybridization (FISH) probes revealed an unbalanced reciprocal translocation between 6q and 17p [46,XX.ish der(6)t(6;17)(q25.3;p13)(TelVysion6q-;TelVysion17p+)]. The second case presented at 25 weeks of gestation with tetralogy of Fallot and at 34 weeks of gestation had additional ultrasound findings of an arachnoid cyst and intrauterine growth restriction. Postnatal karyotyping of peripheral blood was performed and appeared normal. However, a cryptic deletion of the subtelomeric region of the long arm of chromosome 14 was identified when the infant's blood sample was used as a control for an oncology FISH probe. Thereafter, screening of all unique chromosomal subtelomeric regions using a panel of telomere-specific FISH probes revealed an unbalanced reciprocal translocation of chromosomes 14q and 20p [46,XY.ish der(14)t(14;20)(q32.3;p13)(IGH-, D14S308-,TelVysion20p+)mat]. These two cases add to a growing number of reports of cryptic subtelomeric chromosomal rearrangements associated with congenital anomalies. This is the first report of multiple, simultaneous FISH screening of the subtelomeric regions in amniotic fluid and has demonstrated the technical feasibility of this technique in the prenatal period.

Abnormalities, Multiple↗
PubMed2002

Escape from X inactivation.

Although the process of X inactivation in mammalian cells silences the majority of genes on the inactivated X chromosome, some genes escape this chromosome-wide silencing. Genes that escape X inactivation present a unique opportunity to study the process of silencing and the mechanisms that protect some genes from being turned off. In this review, we will discuss evolutionary aspects of escape from X inactivation, in relation to the divergence of the sex chromosomes. Molecular characteristics, expression, and epigenetic modifications of genes that escape will be presented, including their developmental regulation and the implications of chromatin domains along the X chromosome in modeling the escape process.

Animals↗
PubMed2001

Autosomal telomere exchange results in the rapid amplification and dispersion of Csf2ra genes in wild-derived mice.

Common laboratory strains such as C57BL/6J carry a single Csf2ra gene that maps to the distal end of Chromosome (Chr) 19. Here we report that several species of wild mice contain multiple Csf2ra genes. Using interspecific backcross mapping and in situ hybridization, we demonstrate that one of these species, Mus spretus, carries four Csf2ra genes dispersed among the distal tips of Chrs 4, 10, 13, and 19. Our data further suggest that these additional Csf2ra genes are not generated by retrotransposition, but rather by nonhomologous subtelomeric exchanges that could be mediated in part by ribosomal genes located at the subtelomeric regions of Chrs 4, 13, and 19. Although we do not know whether these additional Csf2ra genes are functionally active, our studies suggest that subtelomeric exchange provides a potent means for rapid gene amplification in the mouse.

Animals↗
PubMed2001

Expression and conservation of processed copies of the RBMX gene.

RBMX and RBMY are members of an ancient pair of genes located on the sex chromosomes that encode RNA-binding proteins involved in splicing. These genes have differentiated and evolved separately on the X and Y Chromosomes. RBMY has acquired a testis-specific function, whereas, as shown here, RBMX is ubiquitously expressed and is subject to X inactivation. We have also found that multiple processed copies of RBMX are present in the human genome. RBMX-like sequences (RBMXLs) located on human Chrs 1, 4, 6, 9 (9p13 and 9p24), 11, 20, and X lack introns and thus probably result from retroposition events. We found RBMXLs to be conserved in primates and great apes at corresponding chromosomal locations, indicating that they arose prior to the divergence of human. Some of the RBMXLs show insertions, deletions, and stop codons, which would probably result in nonfunctional proteins. The RBMXL on Chr 20 is deleted in some individuals. Two of the largely intact RBMXLs, located on Chrs 1 and 9p13, are expressed in different tissues and may encode novel proteins involved in splicing in a tissue-specific manner. The RBMXL located at 9p13 is specifically expressed in testis, and to a lesser extent in brain, and may therefore play a role in testis function. This autosomal, testis-specific copy of RBMX could potentially compensate for RBMX that is presumably inactivated in male germ cells, in a manner analogous to autosomal retroposed copies of other X-linked genes.

Amino Acid Sequence↗
PubMed2001

Expression and chromosomal mapping of the mouse smooth muscle calponin gene.

Smooth muscle calponin (Cnn1) is a multifunctional protein whose expression is tightly restricted to differentiated smooth muscle cell (SMC) lineages during embryonic and post-natal life. As such, Cnn1 represents an ideal locus from which to dissect out regulatory elements that control its expression and hence the mature SMC phenotype. Previous work has focused on the expression and chromosomal mapping of the rat and human Cnn1 orthologs. In this report, we describe a unique pattern of Cnn1 expression during the growth and differentiation of BC3H1 cells, a mouse cell line that has transcriptional characteristics of both smooth and skeletal muscle lineages. Actively growing BC3H1 cells exhibit Cnn1 mRNA expression, which is extinguished when these cells are induced to differentiate upon serum withdrawal. Replating differentiated BC3H1 cells restores steady-state Cnn1 mRNA levels. The down-regulation of Cnn1 mRNA during BC3H1 differentiation coincides with the induction of myogenin, a skeletal muscle transcription factor that is not present in SMC lineages. Results from cycloheximide and actinomycin D studies suggest the existence of a labile repressor protein(s) that destabilizes the pool of Cnn1 mRNA and/or silences transcription of the Cnn1 locus. Mapping of the mouse Cnn1 locus to Chr 9, which is homologous to human Cnn1 on 19p13.2 and rat Cnn1 on 8q, suggests no gross rearrangement of this locus in the BC3H1 cell line. These results are the first to show reversible expression of Cnn1 and demonstrate the utility of the BC3H1 muscle cell line as a model system for the further characterization of Cnn1 gene regulation.

Animals↗
PubMed2001

The amnionless gene, essential for mouse gastrulation, encodes a visceral-endoderm-specific protein with an extracellular cysteine-rich domain.

Fate-mapping experiments in the mouse have revealed that the primitive streak can be divided into three functional regions: the proximal region gives rise to germ cells and the extra-embryonic mesoderm of the yolk sac; the distal region generates cardiac mesoderm and node-derived axial mesendoderm; and the middle streak region produces the paraxial, intermediate and lateral plate mesoderm of the trunk. To gain insight into the mechanisms that mediate the assembly of the primitive streak into these functional regions, we have cloned and functionally identified the gene disrupted in the amnionless (amn) mouse, which has a recessive, embryonic lethal mutation that interferes specifically with the formation and/or specification of the middle primitive streak region during gastrulation. Here we report that the gene Amn encodes a novel type I transmembrane protein that is expressed exclusively in the extra-embryonic visceral endoderm layer during gastrulation. The extracellular region of the Amn protein contains a cysteine-rich domain with similarity to bone morphogenetic protein (BMP)-binding cysteine-rich domains in chordin, its Drosophila melanogaster homolog (Short gastrulation) and procollagen IIA (ref. 3). Our findings indicate that Amn may direct the production of trunk mesoderm derived from the middle streak by acting in the underlying visceral endoderm to modulate a BMP signaling pathway.

Amino Acid Sequence↗
PubMed2001

Ring X and other structural X chromosome abnormalities: X inactivation and phenotype.

Patients who carry a structural abnormality of the X chromosome are a fascinating group who have provided opportunities to evaluate genotype/phenotype correlation in relation to X chromosome content and inactivation. Turner syndrome (TS) is most commonly associated with a 45,X karyotype and presents with an array of phenotypes, the main ones being poor viability in utero, ovarian failure and infertility, short stature, lymphedema, and other congenital malformations but usually not mental retardation. In some TS patients the karyotype shows both a normal X and a structurally rearranged X chromosome. These structural abnormalities, which include deletions, duplications, inversions, translocations, and rings, are associated with chromosome breaks and significant imbalance of gene content of the X chromosome. However, such abnormalities are generally well tolerated because of the preferential inactivation of the abnormal X, which can restore, at least in part, a balanced genetic makeup. This beneficial effect of X inactivation results in a mild phenotype in most patients with structural abnormalities of the X, similar to that found in TS patients with a 45,X karyotype. However, in cases of ring X chromosomes and of X/autosome translocations the incidence of mental retardation and other congenital abnormalities can be significantly higher than in TS. These abnormal phenotypes can be ascribed to failed or partial X inactivation and/or incomplete selection in favor of cells with normal balance of gene expression. In this article, we present phenotype/genotype correlation in female patients with structural abnormalities of the X and address the role of X inactivation and cell selection in the phenotypic findings. Our review emphasizes a subset of rare patients with ring X chromosomes who have provided evidence of a direct role for X inactivation in determining phenotypes.

Chromosome Deletion↗
PubMed2000

A novel B lymphocyte-associated adaptor protein, Bam32, regulates antigen receptor signaling downstream of phosphatidylinositol 3-kinase.

We have identified and characterized a novel src homology 2 (SH2) and pleckstrin homology (PH) domain-containing adaptor protein, designated Bam32 (for B cell adaptor molecule of 32 kD). cDNAs encoding the human and mouse Bam32 coding sequences were isolated and the human bam32 gene was mapped to chromosome 4q25-q27. Bam32 is expressed by B lymphocytes, but not T lymphocytes or nonhematopoietic cells. Human germinal center B cells show increased Bam32 expression, and resting B cells rapidly upregulate expression of Bam32 after ligation of CD40, but not immunoglobulin M. Bam32 is tyrosine-phosphorylated upon B cell antigen receptor (BCR) ligation or pervanadate stimulation and associates with phospholipase Cgamma2. After BCR ligation, Bam32 is recruited to the plasma membrane through its PH domain. Membrane recruitment requires phosphatidylinositol 3-kinase (PI3K) activity and an intact PI(3,4, 5)P(3)-binding motif, suggesting that membrane association occurs through binding to 3-phosphoinositides. Expression of Bam32 in B cells leads to a dose-dependent inhibition of BCR-induced activation of nuclear factor of activated T cells (NF-AT), which is blocked by deletion of the PH domain or mutation of the PI(3,4,5)P(3)-binding motif. Thus, Bam32 represents a novel B cell-associated adaptor that regulates BCR signaling downstream of PI3K.

Adaptor Proteins, Signal Transducing↗
PubMed1999

The human acid ceramidase gene (ASAH): structure, chromosomal location, mutation analysis, and expression.

Acid ceramidase (AC) is the lysosomal enzyme that degrades ceramide into sphingosine and fatty acid. A deficiency in human AC activity leads to the lysosomal storage disorder, Farber disease (FD). The human AC gene (HGMW-approved symbol ASAH) was cloned and characterized, revealing an organization similar to that of the murine AC gene. The human gene spans about 30 kb in length and contains 14 exons ranging in size from 46 to 1201 bp. The exon/intron junctions were determined and found to follow the GT-AG rule. The putative promoter region had a GC content over 60%, lacked a TATA box, and contained several sequences matching transcription factor binding sites, including nine SP-1 sites, one AP-1 site, and three CACC boxes. The promoter activity of a 475-bp fragment from within this region was demonstrated by chloramphenicol acyltransferase assays. Northern blotting revealed variable expression of the human AC RNA; i.e., expression of the major 2.4-kb transcript was high in heart and kidney, followed by lung and placenta, but low in pancreas, liver, brain, and skeletal muscle. Two minor AC transcripts of 1.7 and 1.2 kb also were detected in heart and skeletal muscle. The human AC gene was mapped to the chromosomal region 8p21.3-p22 by in situ hybridization and FISH analyses, syntenic with the mouse chromosomal location. Finally, three new missense mutations, E138V, R254G, and P362R, were identified in the human AC gene from FD patients. Mutant AC cDNAs containing these point mutations were constructed and examined using the FLAG-tagged expression system. Although the levels of protein expression for these mutant ACs were about equivalent to that of the controls, their enzymatic activity was markedly reduced, confirming their authenticity.

3T3 Cells↗
PubMed1999

Analysis of a paracentric inversion in human oocytes: nonhomologous pairing in pachytene.

A cytological analysis of the pairing configurations in meiosis in a 19-week human fetus with a de novo paracentric inversion of chromosome 7 (q11.23)(q21.1) is reported, using fluorescent in situ hybridization with a chromosome 7 DNA library, a DNA probe for the centromeric region of chromosome 7, and a probe for the William Syndrome Critical Region (WSCR) at 7q11.23. Of 1079 pachytene cells, 58% exhibited complete heterosynapsis of the inverted region while only 10.3% of cells exhibited the expected loop formation. Meiotic progression was observed to be normal.

Chromosome Inversion↗
PubMed1999

Genetic pathway to recurrent chromosome translocations in murine lymphoma involves V(D)J recombinase.

Chromosome translocations involving antigen receptor loci are a genetic hallmark of non-Hodgkin's lymphomas in humans. Most commonly, these translocations result in juxtaposition of the immunoglobulin heavy-chain (IgH) locus with one of several cellular proto-oncogenes, leading to deregulated oncogene expression. The V(D)J recombinase, which mediates physiologic rearrangements of antigen receptor genes, may play a mechanistic role in some lymphoma translocations, although evidence is indirect. A high incidence of B-lineage lymphomas has been observed in mice with severe combined immunodeficiency (SCID) and p53-null mutations. We show that these tumors are characteristic of the pro-B-cell stage of development and that they harbor recurrent translocations involving chromosomes 12 and 15. Fluorescence in situ hybridization (FISH) shows retention of IgH sequences on the derivative chromosome 12, implying that breakpoints involve the IgH locus. Pro-B-cell lymphomas were suppressed in SCID p53(-/-) mice by a Rag-2-null mutation, demonstrating that DNA breaks generated during V(D)J recombination are required for oncogenic transformation, and suggesting that t(12;15) arise during attempted IgH rearrangement in pro-B cells. These studies indicate that the oncogenic potential inherent in antigen receptor diversification is controlled in vivo by efficient rejoining of DNA ends generated during V(D)J recombination and an intact cellular response to DNA damage.

Animals↗
PubMed1998

Proliferating and migrating mesangial cells responding to injury express a novel receptor protein-tyrosine phosphatase in experimental mesangial proliferative glomerulonephritis.

The mesangial cell provides structural support to the kidney glomerulus. A polymerase chain reaction-based cDNA display approach identified a novel protein-tyrosine phosphatase, rPTP-GMC1, whose transcript expression is transiently and dramatically up-regulated during the period of mesangial cell migration and proliferation that follows mesangial cell injury in the anti-Thy 1 model of mesangial proliferative glomerulonephritis in the rat. In situ hybridization analysis confirmed that rPTP-GMC1 mRNA is up-regulated specifically by mesangial cells responding to the injury and is not detectable in other cells in the kidney or in many normal tissues. In cell culture, rPTP-GMC1 is expressed by mesangial cells but not by glomerular endothelial or epithelial cells (podocytes). The longest transcript (7.5 kilobases) encodes a receptor-like protein-tyrosine phosphatase consisting of a single catalytic domain, a transmembrane segment, and 18 fibronectin type III-like repeats in the extracellular segment. A splice variant predicts a truncated molecule missing the catalytic domain. rPTP-GMC1 maps to human chromosome 12q15 and to the distal end of mouse chromosome 10. The predicted structure of rPTP-GMC1 and its pattern of expression in vivo and in culture suggest that it plays a role in regulating the adhesion and migration of mesangial cells in response to injury.

Amino Acid Sequence↗
PubMed1998

Gene structure and map location of the murine homolog of the Huntington-associated protein, Hap1.

Huntington's Disease (HD) is an inherited progressive neurodegenerative disorder associated with a mutation in a gene expressed in both affected and non-affected tissues. The selective neuropathology in HD is thought to be mediated in part through interactions with other proteins including the Huntington Associated Protein, HAP-1, which is predominantly expressed in the brain. We have mapped its murine homolog, Hap1, to mouse Chr 11 (band D), which shares extensive synteny with human Chr 17 including the region 17q21-q22, where the gene for 'frontotemporal dementia and parkinsonism linked to chromosome 17' has bee mapped. In addition, we have sequenced a 21,984 base pair (bp) genomic clone encompassing the entire Hap1 gene. It is organized as 11 exons and flanked by exons from potentially one or more novel genes. At least three Hap1 transcripts (Hap1-A; Hap1-B; Hap1-C) can be formed by alternative splicing at the 3' end of the gene leading to protein isoforms with novel C-termini.

Algorithms↗
PubMed1998

Comparative methylation analysis of murine transgenes that undergo or escape X-chromosome inactivation.

We analyzed an X-linked metallothionein-vasopressin (MTVP) fusion transgene that undergoes X-chromosome inactivation (X inactivation) and an X-linked transferrin (TFN) transgene that escapes X inactivation with respect to methylation in the 5' regulatory regions. The MTVP transgene promoter region is unmethylated when the transgene is on the active X chromosome and methylated when on the inactive X chromosome. Interestingly, the MTVP transgene is not detectably transcribed from the male X chromosome, although it is unmethylated, consistent with its availability for transcription. The TFN transgene promoter region is hypomethylated on both the active and inactive X chromosomes, consistent with its expression from both chromosomes. The TFN and MTVP transgenes have been mapped to chromosomal regions D and C, respectively, by fluorescence in situ hybridization. These observations are discussed in the context of our understanding of the role of DNA methylation in the spread and maintenance of X-chromosome inactivation.

Animals↗