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991.
Shafqat J Melles E Sigmundsson K Johansson BL Ekberg K Alvelius G Henriksson M Johansson J Wahren J Jörnvall H 《Cellular and molecular life sciences : CMLS》2006,63(15):1805-1811
Using surface plasmon resonance (SPR) and electrospray mass spectrometry (ESI-MS), proinsulin C-peptide was found to influence
insulin-insulin interactions. In SPR with chip-bound insulin, C-peptide mixed with analyte insulin increased the binding,
while alone C-peptide did not. A control peptide with the same residues in random sequence had little effect. In ESI-MS, C-peptide
lowered the presence of insulin hexamer. The data suggest that C-peptide promotes insulin disaggregation. Insulin/insulin
oligomer μM dissociation constants were determined. Compatible with these findings, type 1 diabetic patients receiving insulin
and C-peptide developed 66% more stimulation of glucose metabolism than when given insulin alone. A role of C-peptide in promoting
insulin disaggregation may be important physiologically during exocytosis of pancreatic β-cell secretory granulae and pharmacologically
at insulin injection sites. It is compatible with the normal co-release of C-peptide and insulin and may contribute to the
beneficial effect of C-peptide and insulin replacement in type 1 diabetics.
Received 3 May 2006; received after revision 9 June 2006; accepted 12 June 2006 Free Online Access 相似文献
992.
Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type 总被引:10,自引:0,他引:10
Lerner-Ellis JP Tirone JC Pawelek PD Doré C Atkinson JL Watkins D Morel CF Fujiwara TM Moras E Hosack AR Dunbar GV Antonicka H Forgetta V Dobson CM Leclerc D Gravel RA Shoubridge EA Coulton JW Lepage P Rommens JM Morgan K Rosenblatt DS 《Nature genetics》2006,38(1):93-100
Methylmalonic aciduria and homocystinuria, cblC type (OMIM 277400), is the most common inborn error of vitamin B(12) (cobalamin) metabolism, with about 250 known cases. Affected individuals have developmental, hematological, neurological, metabolic, ophthalmologic and dermatologic clinical findings. Although considered a disease of infancy or childhood, some individuals develop symptoms in adulthood. The cblC locus was mapped to chromosome region 1p by linkage analysis. We refined the chromosomal interval using homozygosity mapping and haplotype analyses and identified the MMACHC gene. In 204 individuals, 42 different mutations were identified, many consistent with a loss of function of the protein product. One mutation, 271dupA, accounted for 40% of all disease alleles. Transduction of wild-type MMACHC into immortalized cblC fibroblast cell lines corrected the cellular phenotype. Molecular modeling predicts that the C-terminal region of the gene product folds similarly to TonB, a bacterial protein involved in energy transduction for cobalamin uptake. 相似文献
993.
Pocsai K Kosztka L Bakondi G Gönczi M Fodor J Dienes B Szentesi P Kovács I Feniger-Barish R Kopf E Zharhary D Szucs G Csernoch L Rusznák Z 《Cellular and molecular life sciences : CMLS》2006,63(19-20):2364-2376
Amplification of the kcnk9 gene and overexpression of the encoded channel protein (TASK-3) seems to be involved in carcinogenesis. In the present work, TASK-3 expression of melanoma cells has been studied. For the investigation of TASK-3-specific immunolabelling, a monoclonal antibody has been developed and applied along with two, commercially available polyclonal antibodies targeting different epitopes of the channel protein. Both primary and metastatic melanoma cells proved to be TASK-3 positive, showing prominent intracellular TASK-3-specific labelling; mostly concentrating around or in the proximity of the nuclei. The immunoreaction was associated with the nuclear envelope, and with the processes of the cells and it was also present in the cell surface membrane. Specificity of the immunolabelling was confirmed by Western blot and transfection experiments. As TASK-3 immunopositivity of benign melanocytes could also be demonstrated, the presence or absence of TASK-3 channels cannot differentiate between malignant and non-malignant melanocytic tumours. 相似文献
994.
The molecular link between β- and γ-secretase activity on the amyloid β precursor protein 总被引:1,自引:1,他引:0
Alzheimer’s disease (AD) is characterized by an accumulation in the brain of amyloid β peptides (Aβ). The production of Aβ
requires two sequential cleavages induced by β- and γ-secretases on the β-amyloid precursor protein (APP). Altered activity
of these secretases is involved in the pathogenesis of AD. The expression and activity of β-secretase (BACE1) is augmented
in the brain in late-onset sporadic AD. Mutant presenilin 1 (PS1), the major genetic defect of early-onset familial AD (FAD),
alters the activity of γ-secretase, leading to increased production of Aβ42. Here we review the role of oxidative stress as
a molecular link between the β- and the γ-secretase activities, and provide a mechanistic explanation of the pathogenesis
of sporadic late-onset AD. We also discuss evidence for a role of the same mechanism in the pathogenesis of familial AD carrying
PS1 mutations. 相似文献
995.
Tsatsanis C Dermitzaki E Venihaki M Chatzaki E Minas V Gravanis A Margioris AN 《Cellular and molecular life sciences : CMLS》2007,64(13):1638-1655
Corticotropin-releasing factor (CRF), also termed corticotropin-releasing hormone (CRH) or corticoliberin, is the major regulator
of the adaptive response to internal or external stresses. An essential component of the adaptation mechanism is the adrenal
gland. CRF regulates adrenal function indirectly through the central nervous system (CNS) via the hypothalamic-pituitary-adrenal
(HPA) axis and via the autonomic nervous system by way of locus coeruleus (LC) in the brain stem. Accumulating evidence suggests
that CRF and its related peptides also affect the adrenals directly, i.e. not through the CNS but from within the adrenal gland where they form paracrine regulatory loops. Indeed, CRF and its related
peptides, the urocortins (UCNs: UCN1, UCN2 and UCN3), their receptors CRF type 1 (CRF1) and 2 (CRF2) as well as the endogenous pseudo-receptor CRF-binding protein (CRF-BP) are all expressed in adrenal cortical, medullary
chromaffin and resident immune cells. The intra-adrenal CRF-based regulatory system is complex and depends on the balance
between the local concentration of CRF ligands and the availability of their receptors.
Received 19 December 2006; received after revision 20 February 2007; accepted 26 March 2007 相似文献
996.
Mailman MD Feolo M Jin Y Kimura M Tryka K Bagoutdinov R Hao L Kiang A Paschall J Phan L Popova N Pretel S Ziyabari L Lee M Shao Y Wang ZY Sirotkin K Ward M Kholodov M Zbicz K Beck J Kimelman M Shevelev S Preuss D Yaschenko E Graeff A Ostell J Sherry ST 《Nature genetics》2007,39(10):1181-1186
The National Center for Biotechnology Information has created the dbGaP public repository for individual-level phenotype, exposure, genotype and sequence data and the associations between them. dbGaP assigns stable, unique identifiers to studies and subsets of information from those studies, including documents, individual phenotypic variables, tables of trait data, sets of genotype data, computed phenotype-genotype associations, and groups of study subjects who have given similar consents for use of their data. 相似文献
997.
Todd JA Walker NM Cooper JD Smyth DJ Downes K Plagnol V Bailey R Nejentsev S Field SF Payne F Lowe CE Szeszko JS Hafler JP Zeitels L Yang JH Vella A Nutland S Stevens HE Schuilenburg H Coleman G Maisuria M Meadows W Smink LJ Healy B Burren OS Lam AA Ovington NR Allen J Adlem E Leung HT Wallace C Howson JM Guja C Ionescu-Tîrgovişte C;Genetics of Type Diabetes in Finland Simmonds MJ Heward JM Gough SC;Wellcome Trust Case Control Consortium Dunger DB Wicker LS Clayton DG 《Nature genetics》2007,39(7):857-864
The Wellcome Trust Case Control Consortium (WTCCC) primary genome-wide association (GWA) scan on seven diseases, including the multifactorial autoimmune disease type 1 diabetes (T1D), shows associations at P < 5 x 10(-7) between T1D and six chromosome regions: 12q24, 12q13, 16p13, 18p11, 12p13 and 4q27. Here, we attempted to validate these and six other top findings in 4,000 individuals with T1D, 5,000 controls and 2,997 family trios independent of the WTCCC study. We confirmed unequivocally the associations of 12q24, 12q13, 16p13 and 18p11 (P(follow-up) 相似文献
998.
Zanke BW Greenwood CM Rangrej J Kustra R Tenesa A Farrington SM Prendergast J Olschwang S Chiang T Crowdy E Ferretti V Laflamme P Sundararajan S Roumy S Olivier JF Robidoux F Sladek R Montpetit A Campbell P Bezieau S O'Shea AM Zogopoulos G Cotterchio M Newcomb P McLaughlin J Younghusband B Green R Green J Porteous ME Campbell H Blanche H Sahbatou M Tubacher E Bonaiti-Pellié C Buecher B Riboli E Kury S Chanock SJ Potter J Thomas G Gallinger S Hudson TJ Dunlop MG 《Nature genetics》2007,39(8):989-994
Using a multistage genetic association approach comprising 7,480 affected individuals and 7,779 controls, we identified markers in chromosomal region 8q24 associated with colorectal cancer. In stage 1, we genotyped 99,632 SNPs in 1,257 affected individuals and 1,336 controls from Ontario. In stages 2-4, we performed serial replication studies using 4,024 affected individuals and 4,042 controls from Seattle, Newfoundland and Scotland. We identified one locus on chromosome 8q24 and another on 9p24 having combined odds ratios (OR) for stages 1-4 of 1.18 (trend; P = 1.41 x 10(-8)) and 1.14 (trend; P = 1.32 x 10(-5)), respectively. Additional analyses in 2,199 affected individuals and 2,401 controls from France and Europe supported the association at the 8q24 locus (OR = 1.16, trend; 95% confidence interval (c.i.): 1.07-1.26; P = 5.05 x 10(-4)). A summary across all seven studies at the 8q24 locus was highly significant (OR = 1.17, c.i.: 1.12-1.23; P = 3.16 x 10(-11)). This locus has also been implicated in prostate cancer. 相似文献
999.
Weedon MN Lettre G Freathy RM Lindgren CM Voight BF Perry JR Elliott KS Hackett R Guiducci C Shields B Zeggini E Lango H Lyssenko V Timpson NJ Burtt NP Rayner NW Saxena R Ardlie K Tobias JH Ness AR Ring SM Palmer CN Morris AD Peltonen L Salomaa V;Diabetes Genetics Initiative;Wellcome Trust Case Control Consortium Davey Smith G Groop LC Hattersley AT McCarthy MI Hirschhorn JN Frayling TM 《Nature genetics》2007,39(10):1245-1250
Human height is a classic, highly heritable quantitative trait. To begin to identify genetic variants influencing height, we examined genome-wide association data from 4,921 individuals. Common variants in the HMGA2 oncogene, exemplified by rs1042725, were associated with height (P = 4 x 10(-8)). HMGA2 is also a strong biological candidate for height, as rare, severe mutations in this gene alter body size in mice and humans, so we tested rs1042725 in additional samples. We confirmed the association in 19,064 adults from four further studies (P = 3 x 10(-11), overall P = 4 x 10(-16), including the genome-wide association data). We also observed the association in children (P = 1 x 10(-6), N = 6,827) and a tall/short case-control study (P = 4 x 10(-6), N = 3,207). We estimate that rs1042725 explains approximately 0.3% of population variation in height (approximately 0.4 cm increased adult height per C allele). There are few examples of common genetic variants reproducibly associated with human quantitativetraits; these results represent, to our knowledge, the first consistently replicated association with adult and childhood height. 相似文献
1000.
Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes 总被引:3,自引:0,他引:3
Kantarci S Al-Gazali L Hill RS Donnai D Black GC Bieth E Chassaing N Lacombe D Devriendt K Teebi A Loscertales M Robson C Liu T MacLaughlin DT Noonan KM Russell MK Walsh CA Donahoe PK Pober BR 《Nature genetics》2007,39(8):957-959
Donnai-Barrow syndrome is associated with agenesis of the corpus callosum, congenital diaphragmatic hernia, facial dysmorphology, ocular anomalies, sensorineural hearing loss and developmental delay. By studying multiplex families, we mapped this disorder to chromosome 2q23.3-31.1 and identified LRP2 mutations in six families with Donnai-Barrow syndrome and one family with facio-oculo-acoustico-renal syndrome. LRP2 encodes megalin, a multiligand uptake receptor that regulates levels of diverse circulating compounds. This work implicates a pathway with potential pharmacological therapeutic targets. 相似文献