A 200-300 kb region of chromosome 3p14.2, including the fragile site locus FRA3B, is homozygously deleted in multiple tumor-derived cell lines. Exon amplification from cosmids covering this deleted region allowed identification of the human FHIT gene, a member of ther histidine triad gene family, which encodes a protein with 69% similarity to an S. pombe enzyme, diadenosine 5', 5''' P1, P4-tetraphosphate asymmetrical hydrolase. The FHIT locus is composed of ten exons distributed over at least 500 kb, with three 5' untranslated exons centromeric to the renal carcinoma-associated 3p14.2 breakpoint, the remaining exons telomeric to this translocation breakpoint, and exon 5 within the homozygously deleted fragile region. Aberrant transcripts of the FHIT locus were found in approximately 50% of esophageal, stomach, and colon carcinomas.
We report cDNA cloning and characterization of the human and mouse orthologs of the chicken YAP (Yes-associated protein) gene which encodes a novel protein that binds to the SH3 (Src homology 3) domain of the Yes proto-oncogene product. Sequence comparison between mouse, human, and chicken YAP proteins showed an inserted sequence in the mouse YAP that represented an imperfect repeat of an upstream sequence. Further analysis of this sequence revealed a putative protein module that is found in various structural, regulatory, and signaling molecules in yeast, nematode, and mammals including human dystrophin. Because one of the prominent features of this sequence motif is two tryptophans (W), we named it the WW domain (Bork, P., and Sudol, M. (1994) Trends Biochem. Sci. 19, 531-533). Since its delineation, more proteins have been shown to contain this domain, and we report here on the widespread distribution of the WW module and present a discussion of its possible function. We have also shown that the human YAP gene is well conserved among higher eukaryotes, but it may not be conserved in yeast. Its expression at the RNA level in adult human tissues is nearly ubiquitous, being relatively high in placenta, prostate, ovary, and testis, but is not detectable in peripheral blood leukocytes. Using fluorescence in situ hybridization on human metaphase chromosomes and by analyzing rodent-human hybrids by Southern blot hybridization and polymerase chain reaction amplification, we mapped the human YAP gene to chromosome band 11q13, a region to which the multiple endocrine neoplasia type 1 gene has been mapped.
A number of vertebrate genes of the Dlx gene family have been cloned in mouse, frog, and zebrafish. These genes contain a homeobox related to that of Distalless, a gene expressed in the developing head and limbs of Drosophila embryos. We cloned and studied the expression of two members of this family, which we amaed DlxS and Dax6, in human and mouse. The two human genes, DLXS and DLX6, are closely linked in an inverted convergent configuration in a region of chromosome 7, at 7q22. Similarly, the two human genes DLXI and DLK2 are closely linked in a convergent configuration at 2q32, near the HOXD (previously HOX4) locus. In situ hybridization experiments in mouse embryos revealed expression of DlxS and Dlx6 mRNA in restricted regions of ventral diencephalon and basal teencephalon, with a distribution very similar to that reported forDMl and Dx2 mRNA. A surprising feature of DlxS and Dlx6 is that they are also expressed in all skeletal sutures of dtion embryos after the first cartilae formation. The expreion pattern of these genes, together with their chromosome calation, may provide useftl cues for the study of congenital disorders in which there is a combination of cranlofacial and limb defects.Many vertebrate genes have been identified by virtue of their nucleotide sequence similarity with Drosophila developmental genes. Many homeobox-containing genes (1) have been identified on this basis. The Dlx gene family (2-7) has been identified because these genes contain a homeobox related to that of Distalless (Dli, also known as Ba) a gene expressed in the head and limbs of the developing fruit fly (8-9).Cloned Dlx sequences in the mouse (2-4), frog (6, 7), and zebrafish (5) have been shown to correspond to at least four different genes, Dlxi-Dlx4. A detailed expression analysis has been carried out for murine Dlxi (2, 10, 11) and Dlx2 (3, 4, 12) genes. They appear to be expressed within the central nervous system of midgestation mouse embryos in specific regions ofthe forebrain, but not in more posterior parts of the neural tube. In early embryos they are also expressed in branchial arches, in the otic vesicle, and in facial and limb primordia. Expression in the developing inner ear has been also reported (5) for the zebrafish cognate of Dlx3. With the notable exception of Xdli2 (7), several frog genes (Xenopus) of the Dlx family have been identified (6, 7) that are similarly expressed in the anterior portion of the embryonic neural tube. In many instances, a correlation of their expression domain with forebrain regionalization (13,14) has been suggested (2)(3)(4)(5)(6)(7)(10)(11)(12) MATERIALS AND METHODSExpression Analysis. A cDNA library prepared from 8-week human embryos (15) was screened at low-stringency conditions with a short Dli genomic sequence including the homeobox (8). Four classes of homologous cDNA clones, corresponding to DLX), DLX2, DLX5, and DLX6, were found. Using these cDNA clones as probes, we screened in turn a human genomic library constructed in cosmids (15) to study the transcrip...
We have previously found linkage to chromosome 1p34 in five large families with autosomal dominant non-syndromic hearing impairment (DFNA2). In all five families, the connexin31 gene ( GJB3 ), located at 1p34 and responsible for non-syndromic autosomal dominant hearing loss in two small Chinese families, has been excluded as the responsible gene. Recently, a fourth member of the KCNQ branch of the K+channel family, KCNQ4, has been cloned. KCNQ4 was mapped to chromosome 1p34 and a single mutation was found in three patients from a small French family with non-syndromic autosomal dominant hearing loss. In this study, we have analysed the KCNQ4 gene for mutations in our five DFNA2 families. Missense mutations altering conserved amino acids were found in three families and an inactivating deletion was present in a fourth family. No KCNQ4 mutation could be found in a single DFNA2 family of Indonesian origin. These results indicate that at least two and possibly three genes responsible for hearing impairment are located close together on chromosome 1p34 and suggest that KCNQ4 mutations may be a relatively frequent cause of autosomal dominant hearing loss.
Genomic alterations influencing the expression and/or activity of tumor suppressors or oncogenes such as KRAS2, CDKN2A, TP53, and DPC4 have been directly implicated in the initiation and progression of human pancreatic adenocarcinoma. In an effort further to systematically characterize the genomic alterations that occur in this disease, we conducted a genome wide analysis of alterations in gene copy number using array-based comparative genomic hybridization (CGH). For this analysis, we utilized a panel of 25 human pancreatic cancer cell lines derived from either primary or metastatic tumors. This panel also included a metastatic progression series of cell lines derived from COLO 357 cells. Array CGH permitted the identification of alterations in the copy number of genes that might participate in the aberrant behavior of pancreatic cancer cells. In addition, the acquisition of invasive and metastatic potential by derivatives of COLO 357 cells was accompanied by additional focal genomic alterations including point mutations and amplification of KRAS2. To complement the array CGH analysis, we also conducted an analysis of mRNA expression patterns in a subset of these cells using cDNA microarrays. By this means, we identified a set of candidate genes, including those regulated by RAS signaling, that may contribute to the process of cancer cell invasion and metastasis. Supplementary material for this article can be found on the Genes, Chromosomes, and Cancer website at http://www.interscience.wiley.com/jpages/1045-2257/suppmat/index.html.
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