Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To construct a framework map of human chromosome 9 consisting of highly informative markers, we identified 36 cosmid clones from chromosome 9 that contained long GT repeat sequences. The cosmids were found to cluster on the long arm of the chromosome, particularly in the q32-34 region. Thirteen highly informative polymorphisms from 9q were identified, with median observed heterozygosity 0.75 and median calculated heterozygosity based upon allele frequencies of 0.75. These new GT repeat polymorphisms (D9S56, D9S58-67), as well as anchor GT polymorphisms for D9S15 (MCT112, 9q13), and ABL and ASS (both 9q34.1) were utilized to construct a linkage map of human 9q by the typing of the Venezuelan Reference Pedigree. Care was taken to avoid errors, including analysis of the data with CHROMLOOK and verification of all double crossover events detected within a 30 cM interval by repetition of the marker analysis. The map was generated using the MAPMAKER program. All positions in the resulting map are favored by odds of greater than 10(4):1. The map has a sex-averaged length of 90 cM (Kosambi function) with a single maximum intermarker recombination fraction of 26%. All other intermarker recombination fractions are less than 15%. As D9S15 is known to be closely linked to markers on proximal 9p, and ASS/ABL are in band 34.1, this set of GT polymorphisms spans the length of 9q and provides a useful panel for linkage analysis of disease genes to this region. The marker order was confirmed by in situ hybridization of the cosmid clones to metaphase spreads of normal human chromosomes, which indicated an excess of recombination in the telomeric region in comparison to centromeric 9q, in agreement with previous chiasmata distribution observations. Two spontaneous new mutations for these GT repeat markers were identified, giving an overall observed spontaneous mutation rate of 0.00045 per locus per gamete. Direct observation of new mutations has not been previously reported for dinucleotide polymorphisms, but the observed rate is consistent with frequencies observed for other VNTR polymorphisms.
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PMID:Construction of a GT polymorphism map of human 9q. 133 84

The DYT1 gene responsible for early-onset, idiopathic torsion dystonia (ITD) in the Ashkenazi Jewish population, as well as in one large non-Jewish family, has been mapped to chromosome 9q32-34. Using (GT)n and RFLP markers in this region, we have identified obligate recombination events in some of these Jewish families, which further delineate the area containing the DYT1 gene to a 6-cM region bounded by loci AK1 and ASS. In 52 unrelated, affected Ashkenazi Jewish individuals, we have found highly significant linkage disequilibrium between a particular extended haplotype at the ABL-ASS loci and the DYT1 gene. The 4/A12 haplotype for ABL-ASS is present on 69% of the disease-bearing chromosomes among affected Jewish individuals and on only 1% of control Jewish chromosomes (chi 2 = 91.07, P much less than .001). The allelic association between this extended haplotype and DYT1 predicts that these three genes lie within 1-2 cM of each other; on the basis of obligate recombination events, the DYT1 gene is centromeric to ASS. Furthermore, this allelic association supports the idea that a single mutation event is responsible for most hereditary cases of dystonia in the Jewish population. Of the 53 definitely affected typed, 13 appear to be sporadic, with no family history of dystonia. However, the proportion of sporadic cases which potentially carry the A12 haplotype at ASS (8/13 [62%]) is similar to the proportion of familial cases with A12 (28/40 [70%]). This suggests that many sporadic cases are hereditary, that the disease gene frequency is greater than 1/15,000, and that the penetrance is lower than 30%, as previously estimated in this population. Most affected individuals were heterozygous for the ABL-ASS haplotype, a finding supporting autosomal dominant inheritance of the DYT1 gene. The ABL-ASS extended-haplotype status will provide predictive value for carrier status in Jewish individuals. This information can be used for molecular diagnosis, evaluation of subclinical expression of the disease, and elucidation of environmental factors which may modify clinical symptoms.
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PMID:Strong allelic association between the torsion dystonia gene (DYT1) andloci on chromosome 9q34 in Ashkenazi Jews. 134 97

We have identified three restriction fragment length polymorphisms (RFLPs) from within the argininosuccinate synthetase (ASS) gene which maps to human chromosome 9q34-qter. Although RFLPs at pseudogene loci are detected by the cDNA, these are the first polymorphisms reported at the ASS locus. The three RFLPs are in linkage equilibrium with each other, and haplotypes for the ASS locus are highly informative. Two-locus recombination estimates between ASS and seven other 9q markers indicated that ASS is closest to the ABO blood group with a recombination fraction of 0.04 (0.005-0.11). A multilocus lod score analysis with these seven 9q markers indicated that ASS maps between ABL and MCT136 close to ABO, but it is uncertain if ASS is centromeric or telomeric to ABO.
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PMID:Multilocus linkage analysis with the human argininosuccinate synthetase gene. 257 81

Gelsolin is a plasma and cytoskeletal protein that severs actin filaments and is regulated by both Ca+2 and polyphosphoinositides. The two forms of gelsolin are encoded by a single gene and derived through alternative message splicing. By Southern blot analysis of somatic cell hybrids and in situ chromosomal localization, we demonstrate that the gelsolin gene is present on human chromosome 9 in bands q32-q34. In situ hybridization of gelsolin to cells containing a Philadelphia chromosome [(9;22)(q34;q11)], as well as Southern blot analysis of K562 cell DNA, indicates that gelsolin is centromeric to the ABL locus in 9q34. Southern blot analysis of NotI-digested, pulsed-field gel electrophoresis-separated DNA indicates the gelsolin gene is greater than or equal to 40 kb centromeric to ABL. These studies and standard Southern blot analysis of digested DNA also indicate that the NotI restriction site contained in the gelsolin gene is uncleavable in DNA from white blood cells and hematopoietic cell lines.
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PMID:Localization of gelsolin proximal to ABL on chromosome 9. 283 14

Leukemic cells from two patients with Philadelphia-negative chronic myeloid leukemia (CML) were investigated: 1) Cytogenetics showed a normal 46,XY karyotype in both cases, 2) molecular studies revealed rearrangement of the M-BCR region and formation of BCR-ABL fusion mRNA with b2a2 (patient 1) or b3a2 (patient 2) configuration, and 3) fluorescence in situ hybridization (FISH) demonstrated relocation of the 5' BCR sequences from one chromosome 22 to one chromosome 9. The ABL probe hybridized to both chromosomes 9 at band q34, while two other probes which map centromeric and telomeric of BCR on 22q11 hybridized solely with chromosome 22. For the first time, a BCR-ABL rearrangement is shown to take place on 9q34 instead of in the usual location on 22q11. A rearrangement in the latter site is found in all Ph-positive CML and in almost all investigated CML with variant Ph or Ph-negative, BCR-positive cases. The few aberrant chromosomal localizations of BCR-ABL recombinant genes found previously were apparently the result of complex and successive changes. Furthermore in patient 2, both chromosomes 9 showed positive FISH signals with both ABL and BCR probes. Restriction fragment length polymorphism (RFLP) analysis indicated that mitotic recombination had occurred on the long arm of chromosome 9 and that the rearranged chromosome 9 was of paternal origin. The leukemic cells of this patient showed a duplication of the BCR-ABL gene, analogous to duplication of the Ph chromosome in classic CML. In addition they had lost the maternal alleles of the 9q34 chromosomal region.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Translocation of BCR to chromosome 9: a new cytogenetic variant detected by FISH in two Ph-negative, BCR-positive patients with chronic myeloid leukemia. 751 67

Deletions of the long arm of chromosome 20 [del(20q)] are recurring abnormalities in patients with myeloid disorders. Although variable in size, these deletions are usually interstitial. With the object of defining a commonly deleted region for smaller 20q deletions, we used quantitative Southern blot analysis complemented by restriction fragment length polymorphism (RFLP) analysis to determine the copy number at 15 loci spanning 20q. The proximal breakpoints of three such deletions were found to separate HCK and the growth hormone releasing factor (GHRF) locus near the centromeric boundary of band 20q11.2. The distal breakpoints were localized to the vicinity of the D20S22 locus in band q13.1. A candidate tumor suppressor gene, RBL2, and the SRC oncogene were both located within the commonly deleted region. Six loci in terminal region q13.2-q13.3 were conserved on these del(20q) chromosomes, thereby confirming that the deletions were interstitial. Molecular heterogeneity at one and possibly both deletion breakpoints rules out the pathological involvement of loci at these sites. Instead, loss of a tumor suppressor locus from within the commonly deleted region may contribute to deregulated hemopoiesis.
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PMID:Molecular heterogeneity at the breakpoints of smaller 20q deletions. 752 43

Trisomy of chromosome 11 (Ts11) is the second most frequent nonrandom chromosomal change in murine plasmacytomas (PCTs). The frequency of Ts11 is significantly higher in PCTs induced in pristane-conditioned mice infected by Abelson-murine leukemia virus (52%) compared to those induced by pristane alone (8.1%). Although the significance of Ts11 in mouse plasmacytomagenesis is not clearly understood it is hypothesized that a gene or genes located on chromosome (Chr) 11 may specifically promote the development of PCTs in which both oncogenes, c-myc and v-abl, are abundantly expressed. To test this assumption we induced PCTs by three highly effective plasmacytomagenic retroviruses: ABL-MYC, J3V1, and RIM. Nearly 90% of PCTs that arose in BALB/c, (BALB/c x DBA/2N)F1, BALB/c-nu/nu, and 5-month-old SCID mice infected with ABL-MYC virus were trisomic for Chr 11. In contrast, < 10% of PCTs induced by J3V1 or RIM retroviral constructs encompassing either v-myc and v-raf or c-myc and v-Ha-ras oncogenes, respectively, contained Ts11. We have also investigated whether the entire Chr 11 or any particular subregion is preferentially duplicated in the process of ABL-MYC plasmacytomagenesis. By inducing PCTs in F1 heterozygous mice that are carriers of reciprocal translocations involving Chr 11 we found that the duplicated chromosomal region is located distal to the T4Dn breakpoint (11B5 band) on the telomeric segment of Chr 11. The regular duplication of this chromosomal segment strongly suggests the presence of a gene or genes whose amplification is of critical importance for v-abl associated murine plasmacytomagenesis.
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PMID:Nonrandom chromosomal change (trisomy 11) in murine plasmacytomas induced by an ABL-MYC retrovirus. 786 5

Acquired deletions of the long arm of chromosome 20 are found in several hematologic conditions and particularly in the myeloproliferative disorders and myelodysplastic syndromes. The spectrum of diseases associated with 20q deletions suggests that such deletions may mark the site of a tumor suppressor gene that contributes to the regulation of normal multipotent hematopoietic progenitors. We present here the first detailed molecular analysis of 20q deletions associated with myeloid disorders. Thirty-four microsatellite primer pairs corresponding to loci on 20q have been used to study DNA samples from two cell lines and from highly purified peripheral blood granulocytes obtained from seven patients. In addition, Southern analysis of cell line DNA has been performed using 19 DNA probes that map to 20q. Three conclusions can be drawn from our results. Firstly, molecular heterogeneity of both centromeric and telomeric breakpoints was demonstrated, thus supporting the existence of a tumor suppressor gene on 20q. In addition many of the breakpoints have been mapped to small genetic intervals. Secondly, our results define a commonly deleted region of 16-21 cM which contains ADA, PLC1, TOP1, SEMG1, and PPGB. Several candidate tumor suppressor genes lie outside the common deleted region including SRC, HCK, p107, PTPN1, and CEBP beta. Thirdly, the data allow integration of genetic and physical maps and have refined the map positions of multiple genes. These results will facilitate attempts to identify candidate hematopoietic tumor suppressor genes on 20q.
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PMID:Molecular analysis of chromosome 20q deletions associated with myeloproliferative disorders and myelodysplastic syndromes. 794 81

Attempts to solve the fundamental questions regarding the descent of man are dogged by superstitions and unexamined orthodoxies. The origin of humans, established a decade ago based upon cytological analysis of ape chromosomes, continues to be called into question. Although molecular methods have provided a framework for tracing the paths of human evolution, conclusive evidence remains elusive. We have used a single ABL gene probe derived from human chromosome 9 to assess the direction of change in the equivalent ape chromosomes. This approach has resulted in a few surprises which again challenge the prevailing view of early primate evolution based solely on chromosome banding patterns. The ABL proto-oncogene is present on human chromosome 9 at band q34. Similar DNA sequences presumed to represent an ABL gene, are present on chromosome 11 in chimpanzee (Pan troglodytes) but at a different relative location, indicating that the mechanism of the origin of human chromosome 9 is far more complex than has previously been suggested. Nevertheless, in gorilla (Gorilla gorilla) and orangutan (Pongo pygmaeus), the equivalent to human chromosome band 9 q34 is apparently located on chromosome 13 at a putative telomeric position and no discernible differences could be established. Despite the presence of the ABL protooncogene on human equivalent ape chromosomes, molecular systematics will continue to generate enigmas in the evolutionary context until the entire genome is sequenced.
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PMID:Evolutionary divergence of human chromosome 9 as revealed by the position of the ABL protooncogene in higher primates. 820 81

We have identified and partially characterized a gene located on chromosome 22, band q11, centromeric of the chronic myelogenous leukemia breakpoint region. A number of overlapping cDNAs were isolated from this locus and the largest of 1.8 kb was sequenced. Its deduced amino acid sequence shows homology to the SH2 domains of protein tyrosine kinases such as FER, and is strikingly similar to the cellular part of the v-crk oncogene product. We identified one SH2 and two SH3 domains within the 303 amino acid open reading frame of this crk-like gene, CRKL. The CRKL gene product is predicted to have a molecular mass of 36 kDa. In addition, we demonstrate that this gene does not represent the human homolog of v-crk but rather a novel gene potentially capable of mediating the transduction of intracellular signals.
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PMID:Isolation and chromosomal localization of CRKL, a human crk-like gene. 836 59


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