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S M Weissman

Publications and source records attributed to S M Weissman.

At least 37 records · Page 2Linked to original sources
PubMed1998

FGFR1 is fused with a novel zinc-finger gene, ZNF198, in the t(8;13) leukaemia/lymphoma syndrome.

Various histological subtypes of leukaemia and lymphoma are associated with diagnostic chromosome translocations, and substantial strides have been made in determining the specific oncogenes targetted by those translocations. We report the cloning of a novel fusion oncogene associated with a unique leukaemia/lymphoma syndrome. Patients afflicted with this syndrome present with lymphoblastic lymphoma and a myeloproliferative disorder, often accompanied by pronounced peripheral eosinophilia and/or prominent eosinophilic infiltrates in the affected bone marrow, which generally progress to full-blown acute myelogenous leukaemia within a year of diagnosis. A specific chromosome translocation, t(8;13)(p11;q11-12), is found in both lymphoma and myeloid leukaemia cells from these patients, supporting bi-lineage differentiation from a transformed stem cell. We find that the 8p11 translocation breakpoints, in each of four patients, interrupt intron 8 of the fibroblast growth factor receptor 1 gene (FGFR1). These translocations are associated with aberrant transcripts in which four predicted zinc-finger domains, contributed by a novel and widely expressed chromosome-13 gene (ZNF198), are fused to the FGFR1 tyrosine-kinase domain. Transient expression studies show that the ZNF198-FGFR1 fusion transcript directs the synthesis of an approximately 87-kD polypeptide, localizing predominantly to the cytoplasm. Our studies demonstrate an FGFR1 oncogenic role and suggest a tumorigenic mechanism in which ZNF198-FGFR1 activation results from ZNF198 zinc-finger-mediated homodimerization.

Amino Acid Sequence↗
PubMed1997

Identification, characterization, and precise mapping of a human gene encoding a novel membrane-spanning protein from the 22q11 region deleted in velo-cardio-facial syndrome.

Velo-cardio-facial syndrome (VCFS) and DiGeorge syndrome (DGS) are characterized by a wide spectrum of phenotypes including cleft palate, conotruncal heart defects, and facial dysmorphology. Hemizygosity for a portion of chromosome 22q11 has been detected in 80-85% of VCFS/DGS patients. Using a cDNA selection protocol, we have identified a new gene, TMVCF (transmembrane protein deleted in VCFS), which maps to the deleted interval. The genomic locus is positioned between polymorphic markers D22S944 and D22S941. TMVCF encodes a small protein of 219 amino acids that is predicted to contain two membrane-spanning domains. TMVCF is expressed abundantly in human adult lung, heart, and skeletal muscle, and transcripts can be detected at least as early as Day 9 of mouse development.

Abnormalities, Multiple↗
PubMed1997

Identification of a new human catenin gene family member (ARVCF) from the region deleted in velo-cardio-facial syndrome.

Velo-cardio-facial syndrome (VCFS) and DiGeorge syndrome (DGS) are characterized by a wide spectrum of phenotypes, including conotruncal heart defects, cleft palate, and facial dysmorphology. Hemizygosity for a portion of chromosome 22q11 has been detected in 80-85% of VCFS/DGS patients. Both syndromes are thought to be the result of a developmental field defect. Using two independent gene-isolation procedures, we isolated a new catenin family member termed ARVCF (armadillo repeat gene deleted in VCFS) from the interval deleted in VCFS. ARVCF encodes a protein of 962 amino acids that contains a coiled coil domain and 10 tandem armadillo repeats. The primary structure of the protein is most closely related to the murine catenin p120CAS, which suggests a role for ARVCF in protein-protein interactions at adherens junctions. ARVCF is expressed ubiquitously in all fetal and adult tissues examined. This gene is hemizygous in all VCFS patients with interstitial deletions. Based on the physical location and potential functions of ARVCF, we suggest that hemizygosity at this locus may play a role in the etiology of some of the phenotypes associated with VCFS.

Abnormalities, Multiple↗
PubMed1997

Molecular definition of 22q11 deletions in 151 velo-cardio-facial syndrome patients.

Velo-cardio-facial syndrome (VCFS) is a relatively common developmental disorder characterized by craniofacial anomalies and conotruncal heart defects. Many VCFS patients have hemizygous deletions for a part of 22q11, suggesting that haploinsufficiency in this region is responsible for its etiology. Because most cases of VCFS are sporadic, portions of 22q11 may be prone to rearrangement. To understand the molecular basis for chromosomal deletions, we defined the extent of the deletion, by genotyping 151 VCFS patients and performing haplotype analysis on 105, using 15 consecutive polymorphic markers in 22q11. We found that 83% had a deletion and >90% of these had a similar approximately 3 Mb deletion, suggesting that sequences flanking the common breakpoints are susceptible to rearrangement. We found no correlation between the presence or size of the deletion and the phenotype. To further define the chromosomal breakpoints among the VCFS patients, we developed somatic hybrid cell lines from a set of VCFS patients. An 11-kb resolution physical map of a 1,080-kb region that includes deletion breakpoints was constructed, incorporating genes and expressed sequence tags (ESTs) isolated by the hybridization selection method. The ordered markers were used to examine the two separated copies of chromosome 22 in the somatic hybrid cell lines. In some cases, we were able to map the chromosome breakpoints within a single cosmid. A 480-kb critical region for VCFS has been delineated, including the genes for GSCL, CTP, CLTD, HIRA, and TMVCF, as well as a number of novel ordered ESTs.

Abnormalities, Multiple↗
PubMed1996

A transcription map of the major histocompatibility complex (MHC) class I region.

We have applied cDNA hybridization selection to nine YACs spanning 3 Mb of genomic DNA from a region centromeric to HLA-A to the histone cluster that lies telomeric to the human major histocompatibility complex (MHC). In addition to Class I genes and pseudogenes, we describe over 63 genes and 23 additional expressed sequence tags distributed throughout the region. Many of the full-length genes belong to gene families. Prominent among these are a group of genes encoding proteins showing homology to the carboxyl-terminal sequences of butyrophilin and an additional group of zinc finger genes. We also detected several previously undefined genes that are specifically expressed in cells of the immune system, indicating a more complex role of the MHC in the immune response than has been appreciated.

Amino Acid Sequence↗
PubMed1996

Multiplex selection technique (MuST): an approach to clone transcription factor binding sites.

We have used a multiplex selection approach to construct a library of DNA-protein interaction sites recognized by many of the DNA-binding proteins present in a cell type. An estimated minimum of two-thirds of the binding sites present in a library prepared from activated Jurkat T cells represent authentic transcription factor binding sites. We used the library for isolation of "optimal" binding site probes that facilitated cloning of a factor and to identify binding activities induced within 2 hr of activation of Jurkat cells. Since a large fraction of the oligonucleotides obtained appear to represent "optimal" binding sites for sequence-specific DNA-binding proteins, it is feasible to construct a catalog of consensus binding sites for DNA-binding proteins in a given cell type. Qualitative and quantitative comparisons of the catalogs of binding site sequences from various cell types could provide valuable insights into the process of differentiation acting at the level of transcriptional control.

Amino Acid Sequence↗
PubMed1996

Analysis of differential gene expression by display of 3' end restriction fragments of cDNAs.

We have developed an approach to study changes in gene expression by selective PCR amplification and display of 3' end restriction fragments of double-stranded cDNAs. This method produces highly consistent and reproducible patterns, can detect almost all mRNAs in a sample, and can resolve hidden differences such as bands that differ in their sequence but comigrate on a gel. Bands corresponding to known cDNAs move to predictable positions on the gel, making this a powerful approach to correlate gel patterns with cDNA data bases. Applying this method, we have examined differences in gene expression patterns during T-cell activation. Of a total of 700 bands that were evaluated in this study, as many as 3-4% represented mRNAs that are upregulated, while approximately 2% were down-regulated within 4 hr of activation of Jurkat T cells. These and other results suggest that this approach is suitable for the systematic, expeditious, and nearly exhaustive elucidation of subtle changes in the patterns of gene expression in cells with altered physiologic states.

Base Sequence↗
PubMed1996

Genes in a 220-kb region spanning the TNF cluster in human MHC.

A search for new genes was performed in a 220-kb region around the tumor necrosis factor gene cluster in the human central major histocompatibility complex region using a cDNA hybridization and selection method. In addition to the seven known genes in this region, we identified a new gene that is preferentially expressed in spleen. We also identified two pseudogenes that have high degrees of homology to cytokeratin and cyclophillin, respectively. Expressed sequences for a human homologue of the mouse B144 gene were also found in the current analysis. RT-PCR analysis showed that B144 is expressed in spleen, in thymus, and prominently in the macrophage cell line, U937. We also independently identified the BAT1 gene to be the well-conserved homologue of a previously described rat liver nuclear protein.

Amino Acid Sequence↗
PubMed1996

Identification of seven new human MHC class I region genes around the HLA-F locus.

Using cDNA hybridization selection techniques, we identified seven new genes in a 280 kilobase YAC covering the HLA-F locus. The new genes were mapped back to the YAC by a combination of optical restriction mapping and pulse field gel electrophoresis. Northern analysis of individual clones demonstrated the presence of either different mRNA sizes or different expression patterns. Two of the cDNA clones were expressed only in lymphoid cell lines: one in Jurkat cells (T cell) and another in JY cells (B cell). All the genes lacked sequence similarity to any known classical and non-classical major histocompatibility complex (MHC) class I genes, indicating that the MHC class I region has more functions than anticipated. Of the seven new genes, one is highly similar (97%) to mouse 60S ribosomal protein, and another is homologous to diubiquitin proteins. Of the two G-coupled receptor-like cDNAs, one was fully sequenced and found to be an olfactory receptor-like gene. The study strengthens evidence that the MHC complex not only plays a key role in the immune system, but also contributes to non-immunological functions.

Animals↗
PubMed1996

Isolation of a new clathrin heavy chain gene with muscle-specific expression from the region commonly deleted in velo-cardio-facial syndrome.

Velo-cardio-facial syndrome (VCFS) and DiGeorge syndrome (DGS) are developmental disorders characterized by a spectrum of phenotypes including velopharyngeal insufficiency, conotruncal heart defects and facial dysmorphology among others. Eighty to eighty-five percent of VCFS/DGS patients are hemizygous for a portion of chromosome 22. It is likely that the genes encoded by this region play a role in the etiology of the phenotypes associated with the disorders. Using a cDNA selection protocol, we isolated a novel clathrin heavy chain cDNA (CLTD) from the VCFS/DGS minimally deleted interval. The cDNA encodes a protein of 1638 amino acids. CLTD shares significant homology, but is not identical to the ubiquitously expressed clathrin heavy chain gene. The CLTD gene also shows a unique pattern of expression, having its maximal level of expression in skeletal muscle. Velopharyngeal insufficiency and muscle weakness are common features of VCFS patients. Based on the location and expression pattern of CLTD, we suggest hemizygosity at this locus may play a role in the etiology of one of the VCFS-associated phenotypes.

Abnormalities, Multiple↗
PubMed1995

A novel Creb family gene telomeric of HLA-DRA in the HLA complex.

cDNA selection was used to identify genes encoded by a 440-kb yeast artificial chromosome (YAC) clone that spanned from HLA-DRA to CYP21 in the HLA complex. An initially selected short cDNA was used to isolate a 2639-nucleotide, apparently full-length cDNA from a human tonsil library. This cDNA contained one extended open reading frame that predicted a protein of 700 amino acids with a basic region and a leucine zipper that is highly similar to members of the Creb/ATF subfamily. High-stringency Southern blotting of total human genomic DNA using this cDNA as the probe showed only a single locus that mapped to the selecting YAC clone. This gene, designated Creb-related protein (Creb-rp), is expressed ubiquitously and is evolutionarily conserved in mammals. It is located in the HLA Class III region 6-10 kb centromeric of the XB gene, which encodes a tenascin-like extracellular matrix protein. Homologous sequences are located in the Class II-Class III interval of the mouse H-2 complex. The amino acid sequence homology and general structural features of the predicted protein indicate that this gene encodes a general transcription factor belonging to the Creb/ATF subfamily of the bZip super-family.

Amino Acid Sequence↗
PubMed1995

A single ataxia telangiectasia gene with a product similar to PI-3 kinase.

A gene, ATM, that is mutated in the autosomal recessive disorder ataxia telangiectasia (AT) was identified by positional cloning on chromosome 11q22-23. AT is characterized by cerebellar degeneration, immunodeficiency, chromosomal instability, cancer predisposition, radiation sensitivity, and cell cycle abnormalities. The disease is genetically heterogeneous, with four complementation groups that have been suspected to represent different genes. ATM, which has a transcript of 12 kilobases, was found to be mutated in AT patients from all complementation groups, indicating that it is probably the sole gene responsible for this disorder. A partial ATM complementary DNA clone of 5.9 kilobases encoded a putative protein that is similar to several yeast and mammalian phosphatidylinositol-3' kinases that are involved in mitogenic signal transduction, meiotic recombination, and cell cycle control. The discovery of ATM should enhance understanding of AT and related syndromes and may allow the identification of AT heterozygotes, who are at increased risk of cancer.

Amino Acid Sequence↗
PubMed1995

A search for genes from the dark band regions of human chromosome 21.

As part of an effort to isolate genes from the entire long arm of human chromosome 21, we performed cDNA selection with 15 YACs from the regions of the pericentromeric heterochromatin and the two Giemsa dark bands of this chromosome using cDNA libraries from six different tissues. Nine of these YACs mapped to the Giemsa dark band, 21q21. The 9 YACs cover approximately 6 Mb of DNA, representing 15% of 21q and a significant portion of the 12-15 Mb estimated to be within this band. Several lines of evidence from analysis of the selected cDNA libraries suggest that this region of 21q has very few single-copy transcribed sequences. An EcoRI library was constructed with DNA from 1 of the 9 YACs. Grail analysis of the sequences of both ends of 24 YAC-specific clones from this EcoRI library revealed no potential exons. In contrast to these results, the selected cDNA libraries of a control YAC from the human MHC region in 6p21.3 as well as those from most of the other 21q YACs consisted largely of YAC-specific single-copy cDNA clones. Given the success of the cDNA selection method for finding a large number of genes in YACs from other chromosomal regions, these results suggest that the 6 Mb of DNA in the dark band 21q21 contains few single-copy sequences expressed in this tissue set. In contrast, selected cDNA libraries from the pericentromeric region, the telomeric border of the dark band 21q21, and the dark band 21q22.2 yielded more than 30 new ESTs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗