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排序方式: 共有93条查询结果,搜索用时 156 毫秒
51.
Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor susceptibility
Astuti D Morris MR Cooper WN Staals RH Wake NC Fews GA Gill H Gentle D Shuib S Ricketts CJ Cole T van Essen AJ van Lingen RA Neri G Opitz JM Rump P Stolte-Dijkstra I Müller F Pruijn GJ Latif F Maher ER 《Nature genetics》2012,44(3):277-284
Perlman syndrome is a congenital overgrowth syndrome inherited in an autosomal recessive manner that is associated with Wilms tumor susceptibility. We mapped a previously unknown susceptibility locus to 2q37.1 and identified germline mutations in DIS3L2, a homolog of the Schizosaccharomyces pombe dis3 gene, in individuals with Perlman syndrome. Yeast dis3 mutant strains have mitotic abnormalities. Yeast Dis3 and its human homologs, DIS3 and DIS3L1, have exoribonuclease activity and bind to the core RNA exosome complex. DIS3L2 has a different intracellular localization and lacks the PIN domain found in DIS3 and DIS3L1; nevertheless, we show that DIS3L2 has exonuclease activity. DIS3L2 inactivation was associated with mitotic abnormalities and altered expression of mitotic checkpoint proteins. DIS3L2 overexpression suppressed the growth of human cancer cell lines, and knockdown enhanced the growth of these cells. We also detected evidence of DIS3L2 mutations in sporadic Wilms tumor. These observations suggest that DIS3L2 has a critical role in RNA metabolism and is essential for the regulation of cell growth and division. 相似文献
52.
Jaeger E Webb E Howarth K Carvajal-Carmona L Rowan A Broderick P Walther A Spain S Pittman A Kemp Z Sullivan K Heinimann K Lubbe S Domingo E Barclay E Martin L Gorman M Chandler I Vijayakrishnan J Wood W Papaemmanuil E Penegar S Qureshi M;CORGI Consortium Farrington S Tenesa A Cazier JB Kerr D Gray R Peto J Dunlop M Campbell H Thomas H Houlston R Tomlinson I 《Nature genetics》2008,40(1):26-28
We mapped a high-penetrance gene (CRAC1; also known as HMPS) associated with colorectal cancer (CRC) in the Ashkenazi population to a 0.6-Mb region on chromosome 15 containing SCG5 (also known as SGNE1), GREM1 and FMN1. We hypothesized that the CRAC1 locus harbored low-penetrance variants that increased CRC risk in the general population. In a large series of colorectal cancer cases and controls, SNPs near GREM1 and SCG5 were strongly associated with increased CRC risk (for rs4779584, P = 4.44 x 10(-14)). 相似文献
53.
Autism Genome Project Consortium Szatmari P Paterson AD Zwaigenbaum L Roberts W Brian J Liu XQ Vincent JB Skaug JL Thompson AP Senman L Feuk L Qian C Bryson SE Jones MB Marshall CR Scherer SW Vieland VJ Bartlett C Mangin LV Goedken R Segre A Pericak-Vance MA Cuccaro ML Gilbert JR Wright HH Abramson RK Betancur C Bourgeron T Gillberg C Leboyer M Buxbaum JD Davis KL Hollander E Silverman JM Hallmayer J Lotspeich L Sutcliffe JS Haines JL Folstein SE Piven J Wassink TH Sheffield V Geschwind DH 《Nature genetics》2007,39(3):319-328
Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 [corrected] families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs. 相似文献
54.
Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility 总被引:14,自引:0,他引:14
Parkes M Barrett JC Prescott NJ Tremelling M Anderson CA Fisher SA Roberts RG Nimmo ER Cummings FR Soars D Drummond H Lees CW Khawaja SA Bagnall R Burke DA Todhunter CE Ahmad T Onnie CM McArdle W Strachan D Bethel G Bryan C Lewis CM Deloukas P Forbes A Sanderson J Jewell DP Satsangi J Mansfield JC;Wellcome Trust Case Control Consortium Cardon L Mathew CG 《Nature genetics》2007,39(7):830-832
A genome-wide association scan in individuals with Crohn's disease by the Wellcome Trust Case Control Consortium detected strong association at four novel loci. We tested 37 SNPs from these and other loci for association in an independent case-control sample. We obtained replication for the autophagy-inducing IRGM gene on chromosome 5q33.1 (replication P = 6.6 x 10(-4), combined P = 2.1 x 10(-10)) and for nine other loci, including NKX2-3, PTPN2 and gene deserts on chromosomes 1q and 5p13. 相似文献
55.
Tartaglia M Pennacchio LA Zhao C Yadav KK Fodale V Sarkozy A Pandit B Oishi K Martinelli S Schackwitz W Ustaszewska A Martin J Bristow J Carta C Lepri F Neri C Vasta I Gibson K Curry CJ Siguero JP Digilio MC Zampino G Dallapiccola B Bar-Sagi D Gelb BD 《Nature genetics》2007,39(1):75-79
Noonan syndrome is a developmental disorder characterized by short stature, facial dysmorphia, congenital heart defects and skeletal anomalies. Increased RAS-mitogen-activated protein kinase (MAPK) signaling due to PTPN11 and KRAS mutations causes 50% of cases of Noonan syndrome. Here, we report that 22 of 129 individuals with Noonan syndrome without PTPN11 or KRAS mutation have missense mutations in SOS1, which encodes a RAS-specific guanine nucleotide exchange factor. SOS1 mutations cluster at codons encoding residues implicated in the maintenance of SOS1 in its autoinhibited form. In addition, ectopic expression of two Noonan syndrome-associated mutants induces enhanced RAS and ERK activation. The phenotype associated with SOS1 defects lies within the Noonan syndrome spectrum but is distinctive, with a high prevalence of ectodermal abnormalities but generally normal development and linear growth. Our findings implicate gain-of-function mutations in a RAS guanine nucleotide exchange factor in disease for the first time and define a new mechanism by which upregulation of the RAS pathway can profoundly change human development. 相似文献
56.
57.
58.
Winckler T Dingermann T Glöckner G 《Cellular and molecular life sciences : CMLS》2002,59(12):2097-2111
Dictyostelium discoideum is a eukaryotic microorganism that is attractive for the study of fundamental biological phenomena such as cell-cell communication,
formation of multicellularity, cell differentiation and morphogenesis. Large-scale sequencing of the D. discoideum genome has provided new insights into evolutionary strategies evolved by transposable elements (TEs) to settle in compact
microbial genomes and to maintain active populations over evolutionary time. The high gene density (about 1 gene/2.6 kb) of
the D. discoideum genome leaves limited space for selfish molecular invaders to move and amplify without causing deleterious mutations that
eradicate their host. Targeting of transfer RNA (tRNA) gene loci appears to be a generally successful strategy for TEs residing
in compact genomes to insert away from coding regions. In D. discoideum, tRNA gene-targeted retrotransposition has evolved independently at least three times by both non-long termina
l repeat (LTR) retrotransposons and retrovirus-like LTR retrotransposons. Unlike the nonspecifically inserting D. discoideum TEs, which have a strong tendency to insert into preexisting TE copies and form large and complex clusters near the ends
of chromosomes, the tRNA gene-targeted retrotransposons have managed to occupy 75% of the tRNA gene loci spread on chromosome
2 and represent 80% of the TEs recognized on the assembled central 6.5-Mb part of chromosome 2. In this review we update the
available information about D. discoideum TEs which emerges both from previous work and current large-scale genome sequencing, with special emphasis on the fact that
tRNA genes are principal determinants of retrotransposon insertions into the D. discoideum genome.
Received 10 May 2002; received after revision 10 June 2002; accepted 12 June 2002
RID="*"
ID="*"Corresponding author. 相似文献
59.
The BRIP1 helicase functions independently of BRCA1 in the Fanconi anemia pathway for DNA crosslink repair 总被引:1,自引:0,他引:1
BRIP1 (also called BACH1) is a DEAH helicase that interacts with the BRCT domain of BRCA1 (refs. 1-6) and has an important role in BRCA1-dependent DNA repair and checkpoint functions. We cloned the chicken ortholog of BRIP1 and established a homozygous knockout in the avian B-cell line DT40. The phenotype of these brip1 mutant cells in response to DNA damage differs from that of brca1 mutant cells and more closely resembles that of fancc mutant cells, with a profound sensitivity to the DNA-crosslinking agent cisplatin and acute cell-cycle arrest in late S-G2 phase. These defects are corrected by expression of human BRIP1 lacking the BRCT-interaction domain. Moreover, in human cells exposed to mitomycin C, short interfering RNA-mediated knock-down of BRIP1 leads to a substantial increase in chromosome aberrations, a characteristic phenotype of cells derived from individuals with Fanconi anemia. Because brip1 mutant cells are proficient for ubiquitination of FANCD2 protein, our data indicate that BRIP1 has a function in the Fanconi anemia pathway that is independent of BRCA1 and downstream of FANCD2 activation. 相似文献
60.
A diffusion barrier maintains distribution of membrane proteins in polarized neurons 总被引:16,自引:0,他引:16
The asymmetric distribution of proteins to distinct domains in the plasma membrane is crucial to the function of many polarized cells. In epithelia, distinct apical and basolateral surfaces are maintained by tight junctions that prevent diffusion of proteins and lipids between the two domains. Polarized neurons maintain axonal and somatodendritic plasma membrane domains without an obvious physical barrier. Indeed, the artificial lipid Dil encounters no diffusion barrier at the presumptive domain boundary, the axon hillock. By measuring the lateral mobility of membrane proteins using optical tweezers, we show here that some membrane proteins exhibit markedly reduced mobility in the initial segment of the axon. Disruption of F-actin and low levels of dimethyl sulphoxide (DMSO) abolish this diffusion barrier and lead to redistribution of membrane markers that had previously been polarized. Immobilization in the initial segment may reflect, at least in part, differential tethering to cytoskeletal components. Therefore, the ability to maintain a polarized distribution of membrane proteins depends on a specialized domain at the initial segment of the axon, which restricts lateral mobility and serves as a new type of diffusion barrier that acts in the absence of cell-cell contact. 相似文献