225 results found
Mahadevappa M, Du F, Durst M, et al., 2000, Gene expression changes in endometrial cancers., AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 67, Pages: 269-269, ISSN: 0002-9297
Wise CA, Herring JA, Shoemaker S, et al., 2000, Evidence of susceptibility loci in genome wide searches of familial idiopathic scoliosis., AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 67, Pages: 359-359, ISSN: 0002-9297
Wise CA, Bennett LS, Pascual V, et al., 2000, Localization of a gene for familial recurrent arthritis, ARTHRITIS AND RHEUMATISM, Vol: 43, Pages: 2041-2045, ISSN: 0004-3591
Swoboda KJ, Soong BW, McKenna C, et al., 2000, Paroxysmal kinesigenic dyskinesia and infantile convulsions - Clinical and linkage studies, NEUROLOGY, Vol: 55, Pages: 224-230, ISSN: 0028-3878
Zhivotovsky LA, Bennett L, Bowcock AM, et al., 2000, Human population expansion and microsatellite variation, MOLECULAR BIOLOGY AND EVOLUTION, Vol: 17, Pages: 757-767, ISSN: 0737-4038
Speckman RA, Garg A, Du FH, et al., 2000, Mutational and haplotype analyses of families with familial partial lipodystrophy (Dunnigan variety) reveal recurrent missense mutations in the globular C-terminal domain of lamin A/C, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 66, Pages: 1192-1198, ISSN: 0002-9297
Bennett LB, Roach ES, Bowcock AM, 2000, A locus for paroxysmal kinesigenic dyskinesia maps to human chromosome 16, NEUROLOGY, Vol: 54, Pages: 125-130, ISSN: 0028-3878
Du F, Weber B, Baer R, et al., 1999, Mutations in sporadic tumors in the BRCA1-interacting protein CtIP and the evaluation of its association with the ubiquituous co-repressor CtBP in mammalian cells., AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 65, Pages: A61-A61, ISSN: 0002-9297
Bennett LB, Roach ES, Bowcock AM, 1999, Localization of Paroxysmal Kinesigenic Dyskinesia (PKD) to chromosome 16p11.2-g11.2., AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 65, Pages: A97-A97, ISSN: 0002-9297
Wise CA, Barnes R, Herring JA, et al., 1999, Genome-wide linkage scan for familial idiopathic scollosis., AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 65, Pages: A102-A102, ISSN: 0002-9297
Gu C, Bowcock AM, 1999, Genetic heterogeneity and epistasis in familial psoriasis: A meta-analysis of genome-wide studies., AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 65, Pages: A252-A252, ISSN: 0002-9297
Garg A, Wilson R, Barnes R, et al., 1999, A gene for congenital generalized lipodystrophy maps to human chromosome 9q34., J Clin Endocrinol Metab, Vol: 84, Pages: 3390-3394, ISSN: 0021-972X
Congenital generalized lipodystrophy (CGL, Berardinelli-Seip Syndrome, OMIM # 269700) is a rare autosomal recessive disorder characterized by near complete absence of adipose tissue from birth. Affected individuals have marked insulin resistance, hypertriglyceridemia and acanthosis nigricans, and develop diabetes mellitus during teenage years. The genetic defect for CGL is unknown. A semi-automated genome-wide scan with a set of highly polymorphic short tandem repeats (STR) was carried out in 17 well-characterized pedigrees and identified a locus for CGL to chromosome 9q34. The maximum two-point lod score obtained was 3.6 at D9S1818 (theta(max) = 0.05). There was evidence for genetic heterogeneity (alpha = 0.73) and 2 of the pedigrees were unlinked. Multipoint linkage analysis excluding the 2 unlinked families yielded a peak lod score of 5.4 between loci D9S1818 and D9S1826. The CGL1 critical region harbors a plausible candidate gene encoding the retinoid X receptor alpha (RXRA) that plays a central role in adipocyte differentiation. Identification of the CGL gene(s) will contribute to our understanding of the adipocyte differentiation and elucidation of the mechanisms of insulin resistance in disorders of adipose tissue.
Ayi TC, Tsan JT, Hwang LY, et al., 1998, Conservation of function and primary structure in the BRCA1-associated RING domain (BARD1) protein., Oncogene, Vol: 17, Pages: 2143-2148, ISSN: 0950-9232
The BRCA1 gene encodes a tumor suppressor that has been implicated in hereditary forms of breast and ovarian cancer. During S phase of the cell cycle, BRCA1 polypeptides are found in discrete nuclear bodies ('BRCA1 nuclear dots') together with HsRad51, a human homolog of the E. coli recA protein, and BARD1, a protein that interacts with BRCA1 to form a stable heterodimer. BARD1 is structurally similar to BRCA1 in that both molecules harbor an amino-terminal RING domain and two carboxy-terminal BRCT domains. Here we describe the amino acid sequence and expression pattern of murine Bard1. A comparison of the mouse and human sequences reveals that the recognizable protein motifs of BARD1 are well conserved, including the RING domain, the three tandem ankyrin repeats, and, to a lesser extent, the two BRCT domains. However, the remaining sequences of BARD1 display a markedly lower degree of phylogenetic conservation, comparable to those reported for BRCA1 and BRCA2. Moreover, murine Bard1 retains the ability to associate in vivo with BRCA1, and its expression pattern in adult mice mirrors that of Brca1, with elevated levels of RNA transcripts found in the testes and spleen. These data suggest that BRCA1 and BARD1 have co-evolved to participate in a common pathway of tumor suppression.
Yu X, Wu LC, Bowcock AM, et al., 1998, The C-terminal (BRCT) domains of BRCA1 interact in vivo with CtIP, a protein implicated in the CtBP pathway of transcriptional repression., J Biol Chem, Vol: 273, Pages: 25388-25392, ISSN: 0021-9258
The BRCA1 tumor suppressor encodes a polypeptide with two recognizable protein motifs: a RING domain near the N terminus and two tandem BRCT domains at the C terminus. Studies of tumor-associated mutations indicate that the RING and BRCT sequences are required for BRCA1-mediated tumor suppression. In addition, recent work has shown that BRCA1 is a potent regulator of RNA transcription and that the BRCT domains are also essential for this activity. Therefore, we used the Sos recruitment system to screen for proteins that bind this critical region of BRCA1. Our results show that the BRCT domains interact in vivo with CtIP, a protein originally identified on the basis of its association with the CtBP transcriptional co-repressor. This finding suggests that BRCA1 regulates gene expression, at least in part, by modulating CtBP-mediated transcriptional repression. Moreover, the in vivo interaction between BRCA1 and CtIP is completely ablated by each of three independent tumor-associated mutations affecting the BRCT motifs of BRCA1. These results indicate that the BRCA1-CtIP interaction may be required for tumor suppression by BRCA1.
Peters JM, Barnes R, Bennett L, et al., 1998, Localization of the gene for familial partial lipodystrophy (Dunnigan variety) to chromosome 1q21-22., Nat Genet, Vol: 18, Pages: 292-295, ISSN: 1061-4036
Obesity is strongly implicated in the pathophysiology of insulin resistance, diabetes mellitus and dyslipidemia. The mechanisms, however, by which obesity causes these complications are not known. The study of single-gene disorders affecting adipose tissue may elucidate some of the mechanisms involved in these processes. Familial partial lipodystrophy, Dunnigan variety, (FPLD, OMIM 308980) is an autosomal-dominant condition characterized by marked loss of subcutaneous adipose tissue affecting the trunk and extremities but with excess fat deposition in the head and neck areas. Affected individuals show an increased preponderance of insulin resistance, diabetes mellitus, dyslipidemia and acanthosis nigricans. The genetic basis of FPLD is unknown. We carried out a genome-wide scan with a set of highly polymorphic short tandem-repeats (STR) in individuals from five well-characterized pedigrees and mapped the FPLD locus to chromosome 1q21-22. The maximum two-point lod score obtained with a highly polymorphic microsatellite at D1S2624 at theta(max)=0 was 5.84. Multipoint-linkage analysis yielded a peak lod score of 8.25 between D1S305 and D1S1600. There was no evidence for genetic heterogeneity (alpha=1) in the pedigrees.
Thai TH, Du F, Tsan JT, et al., 1998, Mutations in the BRCA1-associated RING domain (BARD1) gene in primary breast, ovarian and uterine cancers., Hum Mol Genet, Vol: 7, Pages: 195-202, ISSN: 0964-6906
Germline alterations of BRCA1 result in susceptibility to breast and ovarian cancer. The protein encoded by BRCA1 interacts in vivo with the BRCA1-associated RING domain (BARD1) protein. Accordingly, BARD1 is likely to be a critical factor in BRCA1-mediated tumor suppression and may also serve as a target for tumorigenic lesions in some human cancers. We have now determined the genomic structure of BARD1 and performed a mutational analysis of 58 ovarian tumors, 50 breast tumors and 60 uterine tumors. Seven polymorphisms were detected within the 2.34 kb coding sequence of BARD1 . Somatically acquired missense mutations were observed in one breast carcinoma and one endometrial tumor; in at least one of these cases, tumor formation was accompanied by loss of the wild-type BARD1 allele, following the paradigm for known tumor suppressor genes. In addition, a germline alteration of BARD1 was identified in a clear cell ovarian tumor (Gln564His); again, loss of the wild-type BARD1 allele was observed in the malignant cells of this patient. The Gln564His patient was also diagnosed with two other primary cancers: a synchronous lobular breast carcinoma and a stage IA clear cell endometrioid cancer confined to an endometrial polyp 6 years earlier. These findings suggest an occasional role for BARD1 mutations in the development of sporadic and hereditary tumors.
Bhalerao J, Bowcock AM, 1998, The genetics of psoriasis: a complex disorder of the skin and immune system., Hum Mol Genet, Vol: 7, Pages: 1537-1545, ISSN: 0964-6906
In the last few years, molecular genetics analyses have permitted novel insights into psoriasis, a disease characterized by uncontrolled proliferation of keratinocytes and recruitment of T cells into the skin. The disease affects approximately 1-2% of the Caucasian population and can occur in association with other inflammatory diseases such as Crohn's disease and in association with human immunodeficiency virus (HIV) infection. Given that psoriasis has characteristics of an autoimmune disease, it is not surprising that HLA studies revealed an association with certain alleles, notably HLA-Cw6. Despite this HLA component, psoriasis in some families is inherited as an autosomal dominant trait with high penetrance. Loci at chromosome 17q25 and 4q have been identified following genome-wide linkage scans of large, multiply affected families. In the case of at least the susceptibility locus at 17q25, the development of psoriasis does not require the presence of HLA-Cw6. Sib-pair analyses have confirmed the association with HLA-Cw6, confirmed the existence of a locus at 17q25 and identified other possible susceptibility loci. Two independent groups have reported a third region on chromosome 20p. Despite these findings, the extent of genetic heterogeneity and the role of environmental triggers and modifier genes is still not clear. The precise role of HLA also still needs to be defined. The isolation of novel susceptibility genes will provide insights into the precise biochemical pathways that control this disease. Such pathways will also reveal additional candidate genes that can be tested for molecular alterations resulting in disease susceptibility.
Bennett LB, Shriver MD, Bowcock AM, 1998, Markers and methods for reconstructing modern human history., DNA Seq, Vol: 8, Pages: 329-341, ISSN: 1042-5179
Jin Y, Xu XL, Yang MC, et al., 1997, Cell cycle-dependent colocalization of BARD1 and BRCA1 proteins in discrete nuclear domains., Proc Natl Acad Sci U S A, Vol: 94, Pages: 12075-12080, ISSN: 0027-8424
Germ-line mutations of the BRCA1 gene predispose women to early-onset breast and ovarian cancer by compromising the gene's presumptive function as a tumor suppressor. Although the biochemical properties of BRCA1 polypeptides are not understood, their expression pattern and subcellular localization suggest a role in cell-cycle regulation. When resting cells are induced to proliferate, the steady-state levels of BRCA1 increase in late G1 and reach a maximum during S phase. Moreover, in S phase cells, BRCA1 polypeptides are hyperphosphorylated and accumulate into discrete subnuclear foci termed "BRCA1 nuclear dots." BRCA1 associates in vivo with a structurally related protein termed BARD1. Here we show that the steady-state levels of BARD1, unlike those of BRCA1, remain relatively constant during cell cycle progression. However, immunostaining revealed that BARD1 resides within BRCA1 nuclear dots during S phase of the cell cycle, but not during the G1 phase. Nevertheless, BARD1 polypeptides are found exclusively in the nuclear fractions of both G1- and S-phase cells. Therefore, progression to S phase is accompanied by the aggregation of nuclear BARD1 polypeptides into BRCA1 nuclear dots. This cell cycle-dependent colocalization of BARD1 and BRCA1 indicates a role for BARD1 in BRCA1-mediated tumor suppression.
Barcellos LF, Klitz W, Field LL, et al., 1997, Association mapping of disease loci, by use of a pooled DNA genomic screen, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 61, Pages: 734-747, ISSN: 0002-9297
Kirkpatrick H, Waber P, Hoa-Thai T, et al., 1997, Infrequency of BRCA2 alterations in head and neck squamous cell carcinoma., Oncogene, Vol: 14, Pages: 2189-2193, ISSN: 0950-9232
Alterations of BRCA2 result in increased susceptibility to breast cancer in both men and women (relative lifetime risks of 0.06 and 0.8 respectively). BRCA2 maps to 13q12-q13 and encodes a transcript of 10,157 bp. Other cancers that have been described in BRCA2 mutation carriers include those of the larynx. Human chromosome 13q has been shown previously by LOH studies to harbor several tumor suppressor genes for head and neck squamous cell carcinoma (HNSCCs). We therefore examined the role of BRCA2 in the development of these cancers. Only 6/22 (27%) of the laryngeal cancers we examined demonstrated LOH of the BRCA2-containing region. These and 10 other HNSCCs of different origins that were demonstrated by LOH studies to have lost the region of chromosome 13 containing BRCA2 were examined for alterations in this gene. SSCP analysis failed to reveal any alterations leading us to conclude that BRCA2 alterations are not frequently involved in the pathogenesis of HNSCCs and that the observed LOH of chromosome 13 loci is due to other, as yet, unidentified tumor suppressor gene(s). Interestingly tumors with LOH in this region (proximal to D13S118) were far more likely to be derived from women than men. This is unusual since HNSCCs are usually fourfold more common in men than in women.
Wu LC, Wang ZW, Tsan JT, et al., 1996, Identification of a RING protein that can interact in vivo with the BRCA1 gene product., Nat Genet, Vol: 14, Pages: 430-440, ISSN: 1061-4036
The hereditary breast and ovarian cancer gene, BRCA1, encodes a large polypeptide that contains the cysteine-rich RING motif, a zinc-binding domain found in a variety of regulatory proteins. Here we describe a novel protein that interacts in vivo with the N-terminal region of BRCA1. This BRCA1-associated RING domain (BARD1) protein contains an N-terminal RING motif, three tandem ankyrin repeats, and a C-terminal sequence with significant homology to the phylogenetically conserved BRCT domains that lie near the C terminus of BRCA1. The BARD1/BRCA1 interaction is disrupted by BRCA1 missense mutations that segregate with breast cancer susceptibility, indicating that BARD1 may be involved in mediating tumour suppression by BRCA1.
Spillman MA, Bowcock AM, 1996, BRCA1 and BRCA2 mRNA levels are coordinately elevated in human breast cancer cells in response to estrogen., Oncogene, Vol: 13, Pages: 1639-1645, ISSN: 0950-9232
The steady state levels of BRCA1 and BRCA2 mRNAs were shown to be coordinately elevated by the steroid hormone estrogen but not progesterone in the human breast cancer cell lines BT-483 and MCF-7. Two different antiestrogens, trans 4'-hydroxytamoxifen and ICI 182,780, blocked the elevation of BRCA1 and BRCA2 mRNA levels, confirming that the effect was mediated through the estrogen receptor. In BT-483 cells, BRCA1 and BRCA2 mRNA levels were both elevated 18 to 24 h after estrogen stimulation, suggesting that the effect of estrogen was indirect. Cycloheximide blocked the estrogen effect implying that estrogen induces synthesis of an unidentified estrogen-responsive protein(s) that then result in the elevation of BRCA1 and BRCA2 mRNAs.
Thomson G, Barcellos L, Klitz W, et al., 1996, Association mapping with a pooled DNA genomic screen of the non-HLA genes in IDDM, RA and MS, Publisher: ELSEVIER SCIENCE INC, Pages: P830-P830, ISSN: 0198-8859
Weiss KM, Balmain A, Bodmer W, et al., 1996, Multigenic control of skin tumour development in mice - Discussion, Symposium on Variation in the Human Genome, Publisher: JOHN WILEY & SONS LTD, Pages: 168-180, ISSN: 0300-5208
Chakraborty R, Donnelly P, Bodmer W, et al., 1996, Interpreting genetic variability: The effects of shared evolutionary history - Discussion, Symposium on Variation in the Human Genome, Publisher: JOHN WILEY & SONS LTD, Pages: 40-50, ISSN: 0300-5208
Bowcock AM, Ward RH, Weiss KM, et al., 1996, Phylogeographic variability in traditional societies - Discussion, Symposium on Variation in the Human Genome, Publisher: JOHN WILEY & SONS LTD, Pages: 19-24, ISSN: 0300-5208
Kidd KK, Bodmer J, Freimer NB, et al., 1996, World distribution of HLA alleles and implications for disease - Discussion, Symposium on Variation in the Human Genome, Publisher: JOHN WILEY & SONS LTD, Pages: 253-258, ISSN: 0300-5208
Armour J, Freimer NB, Bodmer W, et al., 1996, Microsatellites: Evolution and mutational processes - Discussion, Symposium on Variation in the Human Genome, Publisher: JOHN WILEY & SONS LTD, Pages: 67-72, ISSN: 0300-5208
Weiss KM, Sutherland GR, Harper PS, et al., 1996, Unusual inheritance patterns due to dynamic mutation in fragile X syndrome - Discussion, Symposium on Variation in the Human Genome, Publisher: JOHN WILEY & SONS LTD, Pages: 126-136, ISSN: 0300-5208
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