Showing papers on "Chromosomal region published in 1999"
TL;DR: The CLV2 gene encodes a receptor-like protein (RLP), with a presumed extracellular domain composed of leucine-rich repeats similar to those found in plant and animal receptors, but with a very short predicted cytoplasmic tail.
Abstract: The CLAVATA2 (CLV2) gene regulates both meristem and organ development in Arabidopsis. We isolated the CLV2 gene and found that it encodes a receptor-like protein (RLP), with a presumed extracellular domain composed of leucine-rich repeats similar to those found in plant and animal receptors, but with a very short predicted cytoplasmic tail. RLPs lacking cytoplasmic signaling domains have not been previously shown to regulate development in plants. Our prior work has demonstrated that the CLV1 receptor-like kinase (RLK) is present as a disulfide-linked multimer in vivo. We report that CLV2 is required for the normal accumulation of CLV1 protein and its assembly into protein complexes, indicating that CLV2 may form a heterodimer with CLV1 to transduce extracellular signals. Sequence analysis suggests that the charged residue in the predicted transmembrane domain of CLV2 may be a common feature of plant RLPs and RLKs. In addition, the chromosomal region in which CLV2 is located contains an extremely high rate of polymorphism, with 50 nucleotide and 15 amino acid differences between Landsberg erecta and Columbia ecotypes within the CLV2 coding sequence.
641 citations
TL;DR: This study, which is the first global research of virulence factors of M. tuberculosis, opens the way to a better understanding of the molecules that are key players in the interaction of this pathogen with its host.
Abstract: Tuberculosis remains the greatest cause of death worldwide due to a single pathogen. In order to identify the genes required for the pathogenicity of Mycobacterium tuberculosis, a functional genomic approach was developed. A library of signature-tagged transposon mutants of this bacterium was constructed and screened for those affected in their multiplication within the lungs of mice. From 1927 mutants tested, 16 were attenuated for their virulence. The insertions harboured by the selected mutants were mapped on the M. tuberculosis genome and most of the mutated loci appeared to be involved in lipid metabolism or transport across the membrane. Four independent mutations identified a cluster of virulence genes located on a 50 kb chromosomal region. These genes might be involved in the production of phthiocerol and phenolphthiocerol derivatives, a group of molecules restricted to eight mycobacterial species, seven of them being either strict or opportunistic pathogens. The interaction of five mutant strains with mouse bone marrow macrophages was investigated. These five mutants were still able to multiply in this cell type. However, in three cases, there was a growth defect in comparison with the wild-type strain. The other two strains exhibited no clear difference from the virulent strain, MT103, in this model. This study, which is the first global research of virulence factors of M. tuberculosis, opens the way to a better understanding of the molecules that are key players in the interaction of this pathogen with its host.
623 citations
TL;DR: O Ongoing mouse ENU mutagenesis experiments are generating a treasure trove of new mutations to allow an in-depth study of a single gene, a chromosomal region or a biological system.
Abstract: The progress of human genome sequencing is driving genetic approaches to define gene function. Strategies such as gene traps and chemical mutagenesis will soon generate a large mutant mouse resource. Point mutations induced by N -ethyl- N -nitrosourea (ENU) provide a unique mutant resource because they: (i) reflect the consequences of single gene change independent of position effects; (ii) provide a fine-structure dissection of protein function; (iii) display a range of mutant effects from complete or partial loss of function to exaggerated function; and (iv) discover gene functions in an unbiased manner. Phenotype-driven ENU screens in the mouse are emphasizing relevance to human clinical disease by targeting cardiology, physiology, neurology, immunity, hematopoiesis and mammalian development. Such approaches are extremely powerful in understanding complex human diseases and traits: the base-pair changes may accurately model base changes found in human diseases, and subtle mutant alleles in a standard genetic background provide the ability to analyze the consequences of compound genotypes. Ongoing mouse ENU mutagenesis experiments are generating a treasure trove of new mutations to allow an in-depth study of a single gene, a chromosomal region or a biological system.
433 citations
TL;DR: The genomic structure of the nephrin gene was analyzed, and 35 NPHS1 patients were screened for the presence of mutations; a total of 32 novel mutations were found; and two common polymorphisms were found.
Abstract: Summary Congenital nephrotic syndrome of the Finnish type (NPHS1) is an autosomal recessive disorder that is caused by mutations in the recently discovered nephrin gene, NPHS1 (AF035835). The disease, which belongs to the Finnish disease heritage, exists predominantly in Finland, but many cases have been observed elsewhere in Europe and North America. The nephrin gene consists of 29 exons spanning 26 kb in the chromosomal region 19q13.1. In the present study, the genomic structure of the nephrin gene was analyzed, and 35 NPHS1 patients were screened for the presence of mutations in the gene. A total of 32 novel mutations, including deletions; insertions; nonsense, missense, and splicing mutations; and two common polymorphisms were found. Only two Swedish and four Finnish patients had the typical Finnish mutations: a 2-bp deletion in exon 2 (Fin major ) or a nonsense mutation in exon 26 (Fin minor ). In seven cases, no mutations were found in the coding region of the NPHS1 gene or in the immediate 5′-flanking region. These patients may have mutations elsewhere in the promoter, in intron areas, or in a gene encoding another protein that interacts with nephrin.
381 citations
TL;DR: The data indicate that mutations in MGP are responsible for KS and confirm its role in the regulation of extracellular matrix calcification and three different mutations predict a non-functional MGP.
Abstract: Keutel syndrome (KS, MIM 245150) is an autosomal recessive disorder characterized by abnormal cartilage calcification, peripheral pulmonary stenosis and midfacial hypoplasia(1). A genome search using homozygosity mapping provided evidence of linkage to chromosome 12p12.3-13.1 (maximum multipoint lod score, 4.06). MGP was a candidate on the basis of its localization to this chromosomal region and the known function of its protein(2-4). MGP maps to chromosome 12p near D12S363 (refs 2,3). Human MCP is a 10-kD skeletal extracellular matrix (ECM) protein that consists of an 84-aa mature protein and a 19-aa transmembrane signal peptide(5). It is a member of the Gla protein family, which includes osteocalcin(6), another skeletal ECM protein, and a number of coagulation factors(7) (factors II, VII, IX, X and proteins S and C). All members of this family have glutamic acid residues modified to gamma-carboxyglutamic acids (Gla) by a specific gamma-carboxylase using Vitamin K as a cofactors(8,9). The modified glutamic acid residues of Gla proteins confer a high affinity for mineral ions such as calcium, phosphate and hydroxyapatite crystals, the mineral components of the skeletal ECM. The pattern and tissue distribution of Mgp expression in mice suggest a role for Mgp in regulating ECM calcification(10). Mglap-deficient mice (Mglap(-/-)) have been reported to have inappropriate calcification of cartilage(4). Mutational analysis of MGP in three unrelated probands identified three different mutations: c.69delG, IVS1-2A-->G and c.113T-->A. All three mutations predict a non-functional MGP. Our data indicate that mutations in MGP are responsible for KS and confirm its role in the regulation of extracellular matrix calcification.
366 citations
TL;DR: Evidence is provided that mutations in PDS cause both syndromic and non-syndromic hearing loss, and seven mutations in the PDS gene (PDS), the gene responsible for Pendred syndrome, have been found in families of non-SYNDromic sensorineural hearing loss with EVA.
Abstract: Enlarged vestibular aqueduct (EVA), known as the most common form of inner ear abnormality, has recently been of particular genetic interest because this anomaly is inherited in a recessive manner. The locus for non-syndromic sensorineural hearing loss with EVA has been mapped to the same chromosomal region, 7q31, as the Pendred syndrome locus. In the present study, seven mutations in the PDS gene (PDS), the gene responsible for Pendred syndrome, have been found in families of non-syndromic sensorineural hearing loss with EVA. One family is homozygous, three families are compound heterozygotes, and two families are heterozygous but with no other mutation detected. The present results provide evidence that mutations in PDS cause both syndromic and non-syndromic hearing loss.
287 citations
TL;DR: Data demonstrate the close genetic similarity of well‐, intermediately, and poorly differentiated DCIS and distinct morphological types of invasive breast carcinoma, providing further evidence that DCIS is a direct precursor lesion ofvasive breast cancer and that various evolutionary genetic pathways exist.
Abstract: Invasive breast cancer shows a wide range of morphological differentiation, associated with differences in prognosis, but as yet, the underlying genetic mechanisms cannot be accounted for. In order to establish a model of the possible progression from the different subtypes of ductal carcinoma in situ (DCIS) to invasive breast cancer, 77 selected cases of invasive breast cancer representing distinct morphological subtypes were investigated by means of comparative genomic hybridization (CGH). There was a high degree of genetic homology between tubular and tubulo-lobular carcinoma and well-differentiated DCIS, and between ductal invasive carcinoma G3 and poorly differentiated DCIS. Highly differentiated invasive breast cancers were characterized by a loss of 16q and a low average number of aberrations per case. In high-grade tumours, losses of this chromosomal region were seen with a much lower frequency in cases with evidence of an aneuploid tumour status. These data demonstrate the close genetic similarity of well-, intermediately, and poorly differentiated DCIS and distinct morphological types of invasive breast carcinoma, providing further evidence that DCIS is a direct precursor lesion of invasive breast cancer and that various evolutionary genetic pathways exist.
266 citations
TL;DR: In this article, the authors identified the TRMA gene by positional cloning and assembled a P1-derived artificial chromosome (PAC) contig spanning the candidate region, and provided 9 new polymorphic markers and narrowed the locus to an approximately 400-kb region.
Abstract: Thiamine-responsive megaloblastic anaemia (TRMA), also known as Rogers syndrome, is an early onset, autosomal recessive disorder defined by the occurrence of megaloblastic anaemia, diabetes mellitus and sensorineural deafness, responding in varying degrees to thiamine treatment1,2 (MIM 249270). We have previously narrowed the TRMA locus from a 16-cM to a 4-cM interval on chromosomal region 1q23.3 (Refs 3, 4) and this region has been further refined to a 1.4-cM interval5. Previous studies have suggested that deficiency in a high-affinity thiamine transporter may cause this disorder6,7. Here we identify the TRMA gene by positional cloning. We assembled a P1-derived artificial chromosome (PAC) contig spanning the TRMA candidate region. This clarified the order of genetic markers across the TRMA locus, provided 9 new polymorphic markers and narrowed the locus to an approximately 400-kb region. Mutations in a new gene, SLC19A2, encoding a putative transmembrane protein homologous to the reduced folate carrier proteins8,9, were found in all affected individuals in six TRMA families, suggesting that a defective thiamine transporter protein (THTR-1) may underlie the TRMA syndrome.
257 citations
TL;DR: Test the causative role of OCTN2 in primary carnitine deficiency by searching for mutations in this gene in affected patients, confirming that defects in the organic cation/carnitine transporter OCTn2 are responsible for primary carnITine deficiency.
Abstract: Primary carnitine deficiency is an autosomal recessive disorder of fatty acid oxidation caused by defective carnitine transport. This disease presents early in life with hypoketotic hypoglycemia or later in life with skeletal myopathy or cardiomyopathy. The gene for this condition maps to 5q31.2–32 and OCTN2, an organic cation/carnitine transporter, also maps to the same chromosomal region. Here we test the causative role of OCTN2 in primary carnitine deficiency by searching for mutations in this gene in affected patients. Fibroblasts from patients with primary carnitine deficiency lacked mediated carnitine transport. Transfection of patient’s fibroblasts with the OCTN2 cDNA partially restored carnitine transport. Sequencing of the OCTN2 gene revealed different mutations in two unrelated patients. The first patient was homozygous (and both parents heterozygous) for a single base pair substitution converting the codon for Arg-282 to a STOP codon (R282X). The second patient was a compound heterozygote for a paternal 1-bp insertion producing a STOP codon (Y401X) and a maternal 1-bp deletion that produced a frameshift creating a subsequent STOP codon (458X). These mutations decreased the levels of mature OCTN2 mRNA and resulted in nonfunctional transporters, confirming that defects in the organic cation/carnitine transporter OCTN2 are responsible for primary carnitine deficiency.
186 citations
TL;DR: Comparison of the phenotype of the DFNB21 heterozygous carriers with that of DFNA8/12-affected individuals supports the hypothesis that the TECTA mutations which cause the dominant form of deafness have a dominant-negative effect, and provides genetic evidence for alpha-tectorin forming homo- or heteromeric structures.
Abstract: In our efforts to identify new loci responsible for non-syndromic autosomal recessive forms of deafness, DFNB loci, we have pursued the analysis of large consanguineous affected families living in geographically isolated areas. Here, we report on the study of a Lebanese family comprising nine members presenting with a pre-lingual severe to profound sensorineural isolated form of deafness. Linkage analysis led to the characterization of a new locus, DFNB21, which was assigned to chromosome 11q23-25. Already mapped to this chromosomal region was TECTA. This gene encodes alpha-tectorin, a 2155 amino acid protein which is a component of the tectorial membrane. This gene recently has been shown to be responsible for a dominant form of deafness, DFNA8/12. Sequence analysis of the TECTA gene in the DFNB21-affected family revealed a G to A transition in the donor splice site (GT) of intron 9, predicted to lead to a truncated protein of 971 amino acids. This establishes that alpha-tectorin mutations can be responsible for both dominant and recessive forms of deafness. Comparison of the phenotype of the DFNB21 heterozygous carriers with that of DFNA8/12-affected individuals supports the hypothesis that the TECTA mutations which cause the dominant form of deafness have a dominant-negative effect. The present results provide genetic evidence for alpha-tectorin forming homo- or heteromeric structures.
181 citations
Journal Article•
TL;DR: Chekmareva et al. as mentioned in this paper identified the mitogenactivated protein kinase kinase 4/stress-activated protein/Erk kinase 1 (MKK4/SEK1) gene as a candidate metastasis suppressor gene encoded by the approximately 70cM region.
Abstract: The introduction of a discontinuous approximately 70-cM portion of human chromosome 17 significantly suppresses the metastatic ability of AT6.1 rat prostate cancer cells without affecting tumorigenicity (M. A. Chekmareva et al., Prostate, 33: 271-280, 1997). We have recently demonstrated that AT6.1 cells containing the approximately 70-cM region (AT6.1-17-4 cells) escape from the primary tumor and arrest in the lung but are growth-inhibited unless the metastasis suppressor region is lost (M. A. Chekmareva et al., Cancer Res., 58: 4963-4969, 1998). A series of in vivo studies indicated that the observed growth inhibition was due to the effect of a gene(s) at the metastatic site (M. A. Chekmareva et al., Cancer Res., 58: 4963-4969, 1998). We have now identified the mitogen-activated protein kinase kinase 4/stress-activated protein/Erk kinase 1 (MKK4/SEK1) gene as a candidate metastasis suppressor gene encoded by the approximately 70-cM region. AT6.1 cells were transfected with a MKK4/SEK1 expression construct, and the cells were tested in standard spontaneous metastasis assays. Whereas the metastatic ability of the AT6.1-MKK4/SEK1 cells was significantly reduced as compared with that of transfection controls, the growth rate of the primary tumors was not affected; the average tumor volume at day 29 after injection was approximately 2 cm. Furthermore, histological examination of the lungs of AT6.1-MKK4/SEK1 tumor-bearing animals revealed that the suppression by MKK4/SEK1 is due to an effect at the metastatic site, consistent with the phenotype conferred by the original approximately 70-cM chromosomal region. These studies implicate MKK4/SEK1 as a metastasis suppressor gene encoded by human chromosome 17.
TL;DR: The different patterns of gene amplification and overexpression of CDK4, SAS and MDM2 in parosteal and intramedullary osteosarcomas may help explain the disparity in the biological behaviour of these two types of osteOSarcoma.
Abstract: Amplification of genes in the 12q13-15 region occurs frequently in several malignancies including osteosarcoma. The products of these amplified genes are thought to provide cancer cells with a selective growth advantage; however, the specific gene(s) driving this amplicon is unknown. We have previously shown that the SAS gene is amplified in most parosteal osteosarcomas. In this study we analysed additional putative growth regulatory genes in this chromosomal region in 24 primary osteosarcoma specimens. CDK4 and SAS were co-amplified in 6/6 parosteal tumors, and MDM2 was also amplified in 4/5 parosteal cases. In comparison, amplification occurred in only 2/16 classical intramedullary osteosarcomas and involved the SAS gene. Each amplified gene had a correspondingly elevated mRNA level. Four high grade intramedullary tumors had elevated mRNA expression of SAS, but did not exhibit gene amplification. Gene amplification/overexpression was not associated with metastatic disease and did not change markedly with tumor progression, as evidenced by analysis of sequential tumor specimens from eight patients. Three other genes in the 12q13-15 region (CDK2, WNT1 and WNT10b) were not amplified in any of the tumors. The different patterns of gene amplification and overexpression of CDK4, SAS and MDM2 in parosteal and intramedullary osteosarcomas may help explain the disparity in the biological behaviour of these two types of osteosarcoma.
TL;DR: A family of nine related genes (50-70% similarity) and their orthologues in species including human, mouse, rat, pig, zebrafish, fruitfly, and nematode is revealed; at least four of these genes occur in the human genome.
TL;DR: In this paper, a linkage analysis in two consanguineous families with sclerosteosis resulted in the assignment of the sclerosis gene to chromosome 17q12-q21.
Abstract: Sclerosteosis is an uncommon, autosomal recessive, progressive, sclerosing, bone dysplasia characterized by generalized osteosclerosis and hyperostosis of the skeleton, affecting mainly the skull and mandible. In most patients this causes facial paralysis and hearing loss. Other features are gigantism and hand abnormalities. In the present study, linkage analysis in two consanguineous families with sclerosteosis resulted in the assignment of the sclerosteosis gene to chromosome 17q12-q21. This region was analyzed because of the recent assignment to this chromosomal region of the gene causing van Buchem disease, a rare autosomal recessive condition with a hyperostosis similar to sclerosteosis. Because of the clinical similarities between sclerosteosis and van Buchem disease, it has previously been suggested that both conditions might be caused by mutations in the same gene. Our study now provides genetic evidence for this hypothesis.
TL;DR: Results suggest that 7q31-q32 loss may be used as a genetic marker of this neoplasia, in conjunction with other morphologic, phenotypic, and clinical features.
Abstract: Splenic marginal zone lymphoma (SMZL) has been recognized as an entity defined on the basis of its morphological, phenotypic, and clinical characteristic features Nevertheless, no characteristic genetic alterations have been described to date for this entity, thus making an exact diagnosis of SMZL difficult in some cases As initial studies showed that chromosome region 7q22-32 is deleted in some of these cases, we analyzed a larger group of SMZL and other lymphoproliferative disorders that may partially overlap with it To better define the frequency of 7q deletion in SMZL and further identify the deleted region, polymerase chain reaction analysis of 13 microsatellite loci spanning 7q21-7q36 was performed on 20 SMZL and 26 non-SMZL tissue samples The frequency of allelic loss in SMZL (8/20; 40%) was higher than that observed in other B-cell lymphoproliferative syndromes (2/26; 77%) This difference was statistically significant (P < 005) The most frequently deleted microsatellite was D7S487 (5/11; 45% of informative cases) Surrounding this microsatellite the smallest common deleted region of 5cM has been identified, defined between D7S685 and D7S514 By comparative multiplex polymerase chain reaction analysis, we detected a homozygous deletion in the D7S685 (7q313) marker in one case These results suggest that 7q31-q32 loss may be used as a genetic marker of this neoplasia, in conjunction with other morphologic, phenotypic, and clinical features A correlation between 7q allelic loss and tumoral progression (death secondary to the tumor or large cell transformation) in SMZL showed a borderline statistical significance The observation of a homozygous deletion in this chromosomal region may indicate that there is a tumor suppressor gene involved in the pathogenesis of this lymphoproliferative neoplasia
TL;DR: The human AC gene was cloned and characterized, revealing an organization similar to that of the murine AC gene, and three new missense mutations, E138V, R254G, and P362R, were identified in thehuman AC gene from FD patients.
TL;DR: Three additional chromosomal regions-4q26-q27, 7p15-p21, and Xcen-also provided some evidence for linkage, and further analyses would be justified to clarify their potential involvement in the genetic predisposition to DIP OA.
Abstract: Summary The genetic contribution to common forms of osteoarthritis (OA) is well established but poorly understood. We performed a genome scan, using 302 markers for loci predisposing to distal interphalangeal joint (DIP) OA. To minimize genetic heterogeneity in our study sample, we identified siblings with a severe, radiologically defined phenotype from the nationwide registers of Finland. In the initial genome scan, linkage analysis in 27 sibships gave a pairwise LOD score ( Z ) >1.00 with nine of the screening markers. In the second stage, additional markers and family members were genotyped in these chromosomal regions. On 2q12-q13, IL1R1 resulted in Z =2.34 at recombination fraction (θ) 0, allowing a dominant mode of inheritance. Association analysis of markers D2S2264, IL1R1, D2S373, and D2S1789 jointly provided some evidence for a shared haplotype among the affected individuals ( P value of .012). Also, multipoint nonparametric linkage analysis yielded a P value of .0001 near the locus IL1R1 and P =.0007 ∼20 cM telomeric near marker D2S1399, which, in two-point analysis, gave Z =1.48 (θ=.02). This chromosomal region on 2q harbors the interleukin 1 gene cluster and, thus, represents a good candidate region for inflammatory and autoimmune disorders. Three additional chromosomal regions—4q26-q27, 7p15-p21, and Xcen—also provided some evidence for linkage, and further analyses would be justified to clarify their potential involvement in the genetic predisposition to DIP OA.
TL;DR: Evidence is provided for a candidate chromosomal region for FCHL and the concept that F CHL is complex and heterogeneous is supported, to help clarify the genetic etiology of the disease.
Abstract: Familial combined hyperlipidemia (FCHL) is a common familial lipid disorder characterized by a variable pattern of elevated levels of plasma cholesterol and/or triglycerides. It is present in 10%-20% of patients with premature coronary heart disease. The genetic etiology of the disease, including the number of genes involved and the magnitude of their effects, is unknown. Using a subset of 35 Dutch families ascertained for FCHL, we screened the genome, with a panel of 399 genetic markers, for chromosomal regions linked to genes contributing to FCHL. The results were analyzed by use of parametric-linkage methods in a two-stage study design. Four loci, on chromosomes 2p, 11p, 16q, and 19q, exhibited suggestive evidence for linkage with FCHL (LOD scores of 1.3-2.6). Markers within each of these regions were then examined in the original sample and in additional Dutch families with FCHL. The locus on chromosome 2 failed to show evidence for linkage, and the loci on chromosome 16q and 19q yielded only equivocal or suggestive evidence for linkage. However, one locus, near marker D11S1324 on the short arm of human chromosome 11, continued to show evidence for linkage with FCHL, in the second stage of this design. This region does not contain any strong candidate genes. These results provide evidence for a candidate chromosomal region for FCHL and support the concept that FCHL is complex and heterogeneous.
TL;DR: Evidence for linkage of bipolar affective disorder to DNA markers on chromosome 18 was reexamined in a large sample of German bipolar families and the findings on 18p11.2 and 18q22–23 support prior evidence for susceptibility loci in these regions.
Abstract: Previously reported linkage of bipolar affective disorder to DNA markers on chromosome 18 was reexamined in a large sample of German bipolar families. Twenty-three short tandem repeat markers were investigated in 57 families containing 103 individuals with bipolar I disorder (BPI), 26 with bipolar II disorder (BPII), nine with schizoaffective disorder of the bipolar type (SA/BP), and 38 individuals with recurrent unipolar depression (UPR). Evidence for linkage was tested with parametric and non-parametric methods under two definitions of the affected phenotype. Analysis of all 57 families revealed no robust evidence for linkage. Following previous reports we performed separate analyses after subdividing the families with respect to the sex of the transmitting parent. Fourteen families were classified as paternal and 12 families as maternal. In 31 families the parental lineage of transmission of the disease could not be determined ('either' families). Evidence for linkage was obtained for chromosomal region 18p11.2 in the paternal families and for 18q22-23 in the 'either' families. The findings on 18p11.2 and 18q22-23 support prior evidence for susceptibility loci in these regions. The parent-of-origin effect on 18p11.2 is confirmed in our sample. The delineation of characteristics of 'either' families requires further study.
TL;DR: The sequence of a 10,879-bp chromosomal region containing at least 12 open reading frames (ORFs), 7 of which are predicted to play a role in enterocin biosynthesis, is presented and the putative EntI peptide was shown to be involved in the immunity to entryocin A.
Abstract: Enterocin A is a small, heat-stable, antilisterial bacteriocin produced by Enterococcus faecium DPC1146. The sequence of a 10,879-bp chromosomal region containing at least 12 open reading frames (ORFs), 7 of which are predicted to play a role in enterocin biosynthesis, is presented. The genes entA, entI, and entF encode the enterocin A prepeptide, the putative immunity protein, and the induction factor prepeptide, respectively. The deduced proteins EntK and EntR resemble the histidine kinase and response regulator proteins of two-component signal transducing systems of the AgrC-AgrA type. The predicted proteins EntT and EntD are homologous to ABC (ATP-binding cassette) transporters and accessory factors, respectively, of several other bacteriocin systems and to proteins implicated in the signal-sequence-independent export of Escherichia coli hemolysin A. Immediately downstream of the entT and entD genes are two ORFs, the product of one of which, ORF4, is very similar to the product of the yteI gene of Bacillus subtilis and to E. coli protease IV, a signal peptide peptidase known to be involved in outer membrane lipoprotein export. Another potential bacteriocin is encoded in the opposite direction to the other genes in the enterocin cluster. This putative bacteriocin-like peptide is similar to LafX, one of the components of the lactacin F complex. A deletion which included one of two direct repeats upstream of the entA gene abolished enterocin A activity, immunity, and ability to induce bacteriocin production. Transposon insertion upstream of the entF gene also had the same effect, but this mutant could be complemented by exogenously supplied induction factor. The putative EntI peptide was shown to be involved in the immunity to enterocin A. Cloning of a 10.5-kb amplicon comprising all predicted ORFs and regulatory regions resulted in heterologous production of enterocin A and induction factor in Enterococcus faecalis, while a four-gene construct (entAITD) under the control of a constitutive promoter resulted in heterologous enterocin A production in both E. faecalis and Lactococcus lactis.
TL;DR: The data show that, in sporadic breast carcinoma, loss of heterozygosity of the PTEN locus is frequent, but mutation of PTEN is not, which is consistent with loss of another unidentified tumour suppressor in this region in sporadic Breast carcinoma.
Abstract: We examined a panel of sporadic breast carcinomas for loss of heterozygosity (LOH) in a 10-cM interval on chromosome 10 known to encompass the PTEN gene. We detected allele loss in 27 of 70 breast tumour DNAs. Fifteen of these showed loss limited to a subregion of the area studied. The most commonly deleted region was flanked by D10S215 and D10S541 and encompasses the PTEN locus. We used a combination of denaturing gradient gel electrophoresis and single-strand conformation polymorphism analyses to investigate the presence of PTEN mutations in tumours with LOH in this region. We did not detect mutations of PTEN in any of these tumours. Our data show that, in sporadic breast carcinoma, loss of heterozygosity of the PTEN locus is frequent, but mutation of PTEN is not. These results are consistent with loss of another unidentified tumour suppressor in this region in sporadic breast carcinoma.
TL;DR: Results suggest that PARP may be (or is close to) the susceptibility gene within the chromosome 1q41-q42 region linked to SLE, and that TGFB2 and HLX1 polymorphisms yielded no evidence for association with SLE.
Abstract: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by various autoantibodies that recognize autoantigens displayed on the surface of cells undergoing apoptosis. The genetic contribution to SLE susceptibility has been widely recognized. We previously reported evidence for linkage to SLE of the human chromosome 1q41‐q42 region and have now narrowed it from 15 to 5 cM in an extended sample using multipoint linkage analysis. Candidate genes within this region include (a) PARP, poly(ADP-ribose) polymerase, encoding a zinc-finger DNA-binding protein that is involved in DNA repair and apoptosis; (b) TGFB2, encoding a transforming growth factor that regulates cellular interactions and responses; and (c) HLX1, encoding a homeobox protein that may regulate T-cell development. Using a multiallelic, transmission-disequilibrium test (TDT), we found overall skewing of transmission of PARP alleles to affected offspring in 124 families (P = 0.00008), preferential transmission of a PARP allele to affected offspring (P = 0.0003), and lack of transmission to unaffected offspring (P = 0.004). Similar TDT analyses of TGFB2 and HLX1 polymorphisms yielded no evidence for association with SLE. These results suggest that PARP may be (or is close to) the susceptibility gene within the chromosome 1q41‐q42 region linked to SLE.
Journal Article•
TL;DR: Northern and Western analyses revealed that amplification of this gene was accompanied by corresponding increases in mRNA and protein expression, respectively, and suggest an oncogenic activity for PS6K.
Abstract: The application of comparative genomic hybridization to the analysis of genetic abnormalities in breast carcinoma has consistently revealed that chromosome region 17q22–24 is a frequent site of gene amplification in this type of cancer. As part of an examination of expressed sequence tags for novel amplified genes in this region, we identified PS6K amplifications in both breast tumor tissues and cell lines. PS6K was localized to 17q23 and encodes a serine-threonine kinase whose activation is thought to regulate a wide array of cellular processes involved in the mitogenic response including protein synthesis, translation of specific mRNA species, and cell cycle progression from G1 to S phase. Northern and Western analyses revealed that amplification of this gene was accompanied by corresponding increases in mRNA and protein expression, respectively. These data represent the first determination of a gene amplification within 17q22–24 in breast cancer and suggest an oncogenic activity for PS6K.
TL;DR: The results indicate that the CD28/CTLA4 gene region can contain a novel susceptibility locus for CD and support the hypothesis that CD has an immune system-mediated component.
Abstract: Celiac disease (CD) is a common small intestinal injury caused by sensitivity to gliadin in genetically-predisposed individuals. The only susceptibility locus established is the HLA-DQ. We tested whether the chromosomal region of the CD28/CTLA4 genes on 2q33 is linked to CD. These genes encode receptors regulating the T-lymphocyte activation. Recently, this gene region was reported to be linked to the susceptibility to many autoimmune diseases, including insulin-dependent diabetes (IDDM12locus). It is thus an obvious candidate locus also for CD, since the intestinal injury is mediated by the immune system. Genetic linkage between seven marker loci in this gene region and CD was studied in 69 Finnish families. In the multipoint linkage analysis, the highest non-pararametric linkage score (NPL) was 1.75 (P=0.04) for D2S116, suggesting weak linkage for this candidate locus. To evaluate this finding, an additional 31 families were typed for all markers. In the combined set of 100 families the NPL score for marker D2S116 was 2.55 (P=0.006) and for other markers 1.90-2.47 (P=0.029-0.007), supporting genuine linkage at this region. Significantly, locus D2S116 also showed a clear allelic association in these 100 families (P=0.0001). The transmission/disequilibrium test (TDT) for locus D2S116 gave preliminary evidence for preferential maternal non-transmission of allele *136 to patients (TDTmax=8.3; P<0.05). No paternal deviation was found suggesting that the effect of the locus might be mediated by a sex-dependent factor protective against CD. Our results indicate that the CD28/CTLA4 gene region can contain a novel susceptibility locus for CD and support the hypothesis that CD has an immune system-mediated component. Like the HLA, the CD28/CTLA4 genes appear to be associated with genetic susceptibility to various autoimmune diseases.
TL;DR: Analysis of non-deletion AS patients has revealed that UBE3A intragenic mutations are found in a significant number of cases and both human patients and mouse model systems indicate that other genes may also contribute to the AS phenotype.
Abstract: Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are two distinct neurological disorders that map to human chromosome 15q11-q13 and involve perturbations of imprinted gene expression PWS is caused by a deficiency of paternal gene expression and AS is caused by a deficiency of maternal gene expression Experiments in the last year have focused on molecular analysis of the human chromosomal region as well as the homologous region on central mouse chromosome 7 New transcripts and exons have been identified and the epigenetic status of the PWS/AS region in mice and humans has been examined The imprinting center that is hypothesized to control the switch between the maternal and paternal epigenotypes has also been characterized in greater detail and a mouse model that deletes the homologous element demonstrates a conservation in imprinting center function between mice and humans In addition, analysis of non-deletion AS patients has revealed that UBE3A intragenic mutations are found in a significant number of cases However, both human patients and mouse model systems indicate that other genes may also contribute to the AS phenotype Thus, although much has been learned in the last year, considerable information is still required before these complex syndromes are fully understood
TL;DR: Cloned Acinetobacter vanA and vanB were shown to be members of a chromosomal segment remote from a supraoperonic cluster containing other genes required for completion of the catabolism of ferulate and its structural analogs, caffeate and coumarate, through protocatechuate.
Abstract: VanA and VanB form an oxygenative demethylase that converts vanillate to protocatechuate in microorganisms. Ferulate, an abundant phytochemical, had been shown to be metabolized through a vanillate intermediate in several Pseudomonas isolates, and biochemical evidence had indicated that vanillate also is an intermediate in ferulate catabolism by Acinetobacter. Genetic evidence supporting this conclusion was obtained by characterization of mutant Acinetobacter strains blocked in catabolism of both ferulate and vanillate. Cloned Acinetobacter vanA and vanB were shown to be members of a chromosomal segment remote from a supraoperonic cluster containing other genes required for completion of the catabolism of ferulate and its structural analogs, caffeate and coumarate, through protocatechuate. The nucleotide sequence of DNA containing vanA and vanB demonstrated the presence of genes that, on the basis of nucleotide sequence similarity, appeared to be associated with transport of aromatic compounds, metabolism of such compounds, or iron scavenging. Spontaneous deletion of 100 kb of DNA containing this segment does not impede the growth of cells with simple carbon sources other than vanillate or ferulate. Additional spontaneous mutations blocking vanA and vanB expression were shown to be mediated by IS1236, including insertion of the newly discovered composite transposon Tn5613. On the whole, vanA and vanB appear to be located within a nonessential genetic region that exhibits considerable genetic malleability in Acinetobacter. The overall organization of genes neighboring Acinetobacter vanA and vanB, including a putative transcriptional regulatory gene that is convergently transcribed and overlaps vanB, is conserved in Pseudomonas aeruginosa but has undergone radical rearrangement in other Pseudomonas species.
TL;DR: Testing for linkage in ADHD families using the functional polymorphism at codon 158 that determines COMT activity and analyzed the data with the transmission disequilibrium test (TDT) finds no evidence for linkage.
Abstract: Attention-deficit hyperactivity disorder is the most common child psychiatric disorder with a prevalence rate in an Ontario study of 9% in boys and 3% in girls [Szatmari et al., 1989]. This disorder is characterized by problems in the areas of attention, overactivity, impulse control, and distractibility. Strong evidence for a genetic component has been provided from twin, family, and adoption studies [for review see Levy et al., 1998] and molecular genetic studies are in progress by several groups worldwide. The Catechol-O-Methyltransferase (COMT) gene is an interesting candidate for ADHD as it is involved in the breakdown of dopamine and norepinephrine, neurotransmitters strongly implicated in the etiology of ADHD. In addition, children with velo-cardio-facial syndrome, a deletion syndrome of the chromosomal region 22q11 where the COMT gene has been localized, often have symptoms of ADHD suggesting this gene may have an etiological role in ADHD. In this study, we have tested for linkage in ADHD families using the functional polymorphism at codon 158 that determines COMT activity [Lachman et al., 1996] and analyzed the data with the transmission disequilibrium test (TDT). A total of 77 nuclear families collected from Toronto were genotyped. We find no evidence for linkage of this polymorphism and ADHD in our sample. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:710-713, 1999.
TL;DR: Findings suggest that DMBT1 may act as a tumour-suppressor gene not only in brain tumours but also in gastrointestinal cancers, especially in oesophageal cancers.
Abstract: Loss of sequences from human chromosome 10q has been reported in several different cancers. Recently, a second candidate tumour-suppressor gene, DMBT1, was identified in this chromosomal region. We studied the mRNA expression and homozygous deletion of this gene in human oesophageal, gastric and colon cancers. Reverse transcriptase polymerase chain reaction (RT-PCR) amplification demonstrated that 23 (53.5%) of 43 oesophageal, 5 (12.5%) of 40 gastric, and 4 (16.7%) of 24 colorectal cancer cases showed an apparent reduction in DMBT1 mRNA in tumour tissues compared with paired normal tissues. Twelve out of 15 oesophageal cancer cell lines also showed no expression. We next studied homozygous deletions within the DMBT1 gene in oesophageal cancers by using duplex PCR. Consequently, it was recognized in five (11.6%) of the primary tumours and two (13.3%) of the cell lines. These findings suggest that DMBT1 may act as a tumour-suppressor gene not only in brain tumours but also in gastrointestinal cancers, especially in oesophageal cancers.
TL;DR: The Bacillus subtilis 168 chromosomal region extending from 184 degrees to 195 degrees, corresponding to prophage SPbeta, has been completely sequenced using DNA of the thermoinducible SPbetac2 mutant, and this 134416 bp segment comprises 187 putative ORFs which, according to their orientation, were grouped into three clusters.
Abstract: The Bacillus subtilis 168 chromosomal region extending from 184° to 195°, corresponding to prophage SPβ, has been completely sequenced using DNA of the thermoinducible SPβc2 mutant. This 134416 bp segment comprises 187 putative ORFs which, according to their orientation, were grouped into three clusters. Compared to its host, SPβc2 is characterized by a lower G+C content, shorter mean ORF length, as well as a different usage of start codons. Nearly 75% of predicted ORFs do not share significant homologies to sequences in available databases. The only highly similar proteins to SPβc2-encoded ones are host paralogues. SPβc2 promoter regions contain SOS box consensus sequences and a repeated motif, designated SPβ repeated element (SPBRE), that is absent from the host genome. Gene sspC, encoding the small acid-soluble protein C, that has been previously sequenced and mapped to the vicinity of the SPβ region, was found to be part of the prophage.
TL;DR: Resistance to SDS DX, SDS IS and SCN IP in Forrest may be caused by four genes in a cluster with two pairs in close linkage or by a two-gene cluster with each gene displaying pleiotropy, one conditioning SDSIS and DX and the other SCNIP and SDSDX.
Abstract: In the soybean [Glycine max (L.) Merr.] cultivar ’Forrest’ a single chromosomal region underlies co-inheritance of field resistance of the sudden-death syndrome (SDS), caused by the fungus Fusarium solani (Mart.) Sacc. f. sp. glycines (Burk.) Snyd. & Hans. and soybean cyst nematode (SCN) race 3 (caused by Heterodera glycines Ichinohe). Our objectives were to verify that co-inheritance was derived from a single chromosomal region in near-isogenic lines and to separate component gene clusters. DNA markers were compared with a SDS leaf-scorch index (DX), F. solani root-infection severity (IS) and a SCN index of parasitism (IP) among 80 near-isogenic lines (NILs). The genomic region identified by the RFLP marker Bng122D was strongly associated (0.0004 ≤P≤ 0.006) with mean SDS DX (R
2 > 16–38%) and IS (R
2 > 38–73%), but only marginally associated with resistance to SCN. However, the linked (4.3–7.4 cM) microsatellite marker SATT309 was strongly associated with both resistance to SCN (0.0001 ≤P≤ 0.0003; R
2 > 24–97%) and mean leaf DX (0.0001 ≤P≤ 0.0003; R
2 > 25–63%), but not root IS. Recombination events among markers and traits enabled separation of the qualitative loci underlying resistance to SDS and SCN. Our data showed that resistance to SDS DX, SDS IS and SCN IP in Forrest may be caused by four genes in a cluster with two pairs in close linkage or by a two-gene cluster with each gene displaying pleiotropy, one conditioning SDS IS and DX and the other SCN IP and SDS DX.