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:2.6.1.44 (AGT)
770 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuroserpin isolated from inclusion bodies in the brain of a patient with a neurodegenerative disease was characterized biochemically. The protein consisted of residues 20 to 410 of the neuroserpin precursor deduced from its cDNA sequence indicating the entire molecule was deposited. A minor amount started with residue 19 of the precursor, and the carboxyl terminus was heterogeneous ending at residues 405, 407, 409, and 410. Arg was present at position 52. No normal Ser52 was found indicating that only mutant neuroserpin was present in the inclusion bodies. The three potential Asn glycosylation sites all contained carbohydrate. DNA sequence analysis of exons 2 to 9 of the neuroserpin gene in the proband showed the published normal neuroserpin sequence except for the presence of both adenine and cytosine at the first position of codon 52, that indicates heterozygosity for both the normal Ser(AGT) and variant Arg(CGT) at this position in the expressed protein. Restriction fragment length polymorphism analysis of a polymerase chain reaction product from exon 2 revealed the propositus and his affected sibling both were heterozygous for the mutation whereas 100 unaffected controls were negative. Chemical characterization of the variant neuroserpin will significantly enhance the understanding of this protein in both normal physiology and neurodegenerative diseases.
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PMID:Biochemical characterization of a neuroserpin variant associated with hereditary dementia. 1114 96

We describe Japanese siblings with resistance to thyrotropin (TSH) who are compound heterozygotes for two novel mutations in the TSH receptor gene. The affected siblings had increased serum TSH, normal serum thyroid hormones, and normal positioned but slightly hypoplastic thyroid glands. The mutated paternal allele has the substitution of His (CAC) in place of Arg (CGC) at codon 450 (R450H) of the TSH receptor. The mutated maternal allele has the substitution of Ser (AGT) in place of Gly (GGT) at codon 498 (G498S) of the TSH receptor. COS-7 cells transfected with the R450H mutant exhibited a slightly decreased TSH binding and a slightly decreased cyclic adenosine monophosphate (cAMP) response to TSH, whereas cells transfected with the G498S mutant exhibited a markedly decreased TSH binding and a markedly decreased cAMP response to TSH. Flow immunocytofluorometry analysis demonstrated that the G498S mutant resulted in extremely low expression at the cell surface as compared with the wild type receptor and the R450H mutant, in spite of a normal intracellular synthesis. The present cases are the first Japanese patients with TSH resistance in whom mutations in the TSH receptor gene have been identified. These novel mutations may contribute to understanding of the struc-ture-function relationship of the TSH receptor.
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PMID:Novel inactivating missense mutations in the thyrotropin receptor gene in Japanese children with resistance to thyrotropin. 1144 2

It has previously been demonstrated that accumulated beta-catenin serves as an oncoprotein in synovial sarcoma and results in a poor overall survival rate, but the frequency of beta-catenin mutation was quite low (8.2%). The present study, using essentially the same study group of cases, screened for genetic alterations in the mutation cluster region (MCR) of the APC gene in 49 cases of synovial sarcoma. SSCP analysis followed by DNA direct sequencing revealed five missense APC mutations in four cases of synovial sarcoma (8.2%). The mutational sites comprised one case each at codons 1299 (GCT to ACT, Ala to Thr), 1412 (GGA to AGA, Gly to Arg), and 1414 (GTA to ATA, Val to Ile), in addition to one case with double point mutations at codon 1398 (AGT to AAT, Ser to Asn) and at codon 1413 (ATG to ATA, Met to Ile), together with beta-catenin mutation at codon 32 (GAC to TAC, Asp to Tyr). All four cases with APC mutations were histologically of the monophasic fibrous type and showed beta-catenin accumulation. All three cases with APC mutations available for follow-up data were long survivors. This study provides the first evidence that APC mutations also occur in the field of sarcoma, especially in synovial sarcoma.
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PMID:APC mutations in synovial sarcoma. 1192 Jul 41

K-ras mutation is the most common oncogenic alteration in various human cancers including colorectal carcinomas. Point mutations have the potential to activate the K-ras gene if they occur in the critical coding sequences. Almost all of these mutations have been localized in codons 12, 13 and 61. We report a case of colon cancer presenting point mutations at both codons 12 and 22 of the K-ras gene. PCR-SSCP and subsequent sequencing revealed that GGT (glycine, wild-type) to AGT (serine) substitution at codon 12 and CAG (glutamine, wild-type) to CGG (arginine) substitution at codon 22 occurred in the same allele.
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PMID:Concurrent mutations of K-ras oncogene at codons 12 and 22 in colon cancer. 1211 Jun 40

We report on a 15-year-old girl who presented with pituitary hypoplasia, os odontoideum, renal dysplasia, an asymmetrically short right leg, and postaxial hypodactyly of the right foot. Her endocrinological data showed anterior pituitary hormone deficiency. The fact that she had healthy parents and an elder sister suggests that she had either a de novo mutation or autosomal recessive inheritance. We speculated that bone morphogenetic protein 4 (BMP4), BMP2, or pituitary homeobox 1 (PTX1) might be the responsible genes in this patient based on the similarity of her clinical symptoms and phenotypes to knock-out mice of these genes. We performed mutation analysis of these genes by direct sequencing of genomic DNA. In BMP2 gene, AGA right curved arrow AGT transversion in exon 3, converting arginine to serine was detected. In PTX1 gene, transversion of GCC right curved arrow GGC in exon 2, converting alanine to glycine at codon 184 was found in the patient and controls. We did not find any non-sense mutations although 5 polymorphisms of these genes were found. This constellation of findings may represent a new entity of congenital combined pituitary hormone deficiency.
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PMID:Lack of aberrations of the BMP4, BMP2, and PTX1 genes in a patient with pituitary hypoplasia, os odontoideum, renal dysplasia, and right leg anomalies. 1216 3

The aim of this study was to identify K-ras mutations as marker for isolated tumor cells in liver, lymph node, and bone marrow specimens of colorectal cancer patients. To detect these, a PCR-RFLP assay was used with a sensitivity exceeding that of routine histopathology by at least 1 order of magnitude. In addition, the ratio of mutated versus wild-type alleles was determined by an internal standard. Of 199 patients, 74 (37.5%) were found to bear a K-ras-positive tumor. Of these, 60 (81%) were mutated in codon 12 and 14 (19%) in codon 13 (P < 0.001). In addition, 14 organs were found K-ras positive, 13 of which were from 12 patients with a K-ras-positive tumor (16%) and 1 from a patient with a K-ras-negative tumor (0.8%). Eight patients exhibited liver involvement and 6 showed lymph node involvement. Remarkably, no bone marrow specimen was found K-ras positive (P < 0.017 versus liver involvement). Sequence analysis of tumor DNA revealed that GGT (Gly) was replaced by GAT (Asp; 35%), GTT (Val; 32%), AGT (Ser; 13%), GCT (Ala; 10%), TGT (Cys; 8%), and CGT (Arg; 2%) for codon 12, and by GAC (Asp) as the only type of mutation for codon 13. In colorectal carcinomas the ratio of K-ras mutated versus wild-type alleles ranged over 4 orders of magnitude (10(0)-10(-4), median: 10(-2)) and was correlated with both, residual tumor load (R1/2; P = 0.028) and distant metastasis (M1; P = 0.057). These results show that detection of K-ras mutated alleles by PCR-RFLP in patients with colorectal carcinoma may aid in the identification of isolated tumor cells. High ratios of K-ras alleles were correlated with certain negative prognostic parameters (R,M). In accord with its function as a primary filter for colorectal carcinoma cells, the liver was more often contaminated with K-ras-positive cells than bone marrow.
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PMID:Detection of isolated tumor cells by polymerase chain reaction-restriction fragment length polymorphism for K-ras mutations in tissue samples of 199 colorectal cancer patients. 1476 87

Hepatocellular carcinoma (HCC) is frequent in areas of high exposure to aflatoxin and high prevalence of HBV infection, such as western Africa and south-east China. A selective mutation in TP53 (AGG-->AGT at codon 249, Arg-->Ser) has been identified as a hotspot in HCCs from such areas, reflecting DNA damage caused by aflatoxin metabolites. Recent studies have shown that circulating free DNA can be retrieved from human plasma, and it is hypothesised that plasma DNA may serve as a source for biomarkers of tumorigenic processes. In our study, we have determined the prevalence of Ser-249 mutation, using a PCR-restriction digestion method, with selective use of short oligonucleotide mass spectrometry analysis (SOMA), in a series of 29 biopsy specimens of HCC from The Gambia in West Africa. Overall, we identified the Ser-249 mutation in 35% (10/29) of the tumours. In parallel, we tested 17 plasma samples from HCC patients with matching tumour tissue. The 249 status concordance between tumour tissues and matched plasma was 88.5%. These results indicate that the Ser-249 mutation is common in HCC in The Gambia (35%), although a higher prevalence has been reported in other regions with high population exposure to aflatoxin (e.g., eastern China: >50%). Moreover, our studies indicate that plasma is a convenient source of liver tumour-derived DNA, thus holding promise for earlier detection and diagnosis of cancer.
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PMID:Ser-249TP53 mutation in tumour and plasma DNA of hepatocellular carcinoma patients from a high incidence area in the Gambia, West Africa. 1509 2

For Matthiola incana (Brassicaceae), used as a model system to study biochemical and genetical aspects of anthocyanin biosynthesis, several nearly isogenic colored wild type lines and white-flowering mutant lines are available, each with a specific defect in the genes responsible for anthocyanin production (genes e, f, and g). For gene f supposed to code for chalcone synthase (CHS; EC 2.3.1.74), the key enzyme of the flavonoid/anthocyanin biosynthesis pathway belonging to the group of type III polyketide synthases (PKS), the wild type genomic sequence of M. incana line 04 was determined in comparison to the white-flowering CHS mutant line 18. The type of mutation in the chs gene was characterized as a single nucleotide substitution in a triplet AGG coding for an evolutionary conserved arginine into AGT coding for serine (R72S). Northern blots and RT-PCR demonstrated that the mutated gene is expressed in flower petals. Heterologous expression of the wild type and mutated CHS cDNA in E. Scherichia coli, verified by Western blotting and enzyme assays with various starter molecules, revealed that the mutant protein had no detectable activity, indicating that the strictly conserved arginine residue is essential for the enzymatic reaction. This mutation, which previously was not detected by mutagenic screening, is discussed in the light of structural and functional information on alfalfa CHS and related type III PKS enzymes.
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PMID:Characterization and structural features of a chalcone synthase mutation in a white-flowering line of Matthiola incana R. Br. (Brassicaceae). 1560 92

Hepatocellular carcinoma (HCC) from regions with high dietary exposure to aflatoxins and endemic for hepatitis B virus (HBV) often contain a specific mutation at codon 249 in TP53 (249(ser); AGG to AGT, Arg to Ser). This mutation is also detectable in circulating cell-free DNA from the plasma of HCC patients and healthy subjects in these regions. We have examined the joint effect of plasma 249(ser) and HBV infection in a case-control study design involving 348 control, 98 cirrhotic, and 186 HCC participants from The Gambia, West Africa, an area of high HCC incidence. The 249(ser) mutation was detected in 3.5% of controls, 15.3% of cirrhotics, and 39.8% of HCC cases (adjusted odds ratios (OR): 4.83, (95% confidence interval (CI): 1.71-13.7) for cirrhosis and 20.3 (8.19-50.0) for HCC). HBsAg positivity along with plasma 249(ser) was observed in 45/183 (24.6%) HCC cases compared to only one (0.3%) control. Risk for HCC was associated with markers of HBV alone (OR: 10.0, 95% CI: 5.16-19.6), 249(ser) alone (OR: 13.2, 95% CI: 4.99-35.0), and both markers present (OR: 399, 95% CI: 48.6-3270). These results suggest a multiplicative effect on HCC risk resulting from the mutational effect of aflatoxin on TP53, as monitored by detection of plasma 249(ser), with concomitant chronic infection with HBV.
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PMID:249(ser) TP53 mutation in plasma DNA, hepatitis B viral infection, and risk of hepatocellular carcinoma. 1600 11

A 61-year-old man with no subjective symptom was admitted to our hospital for further examination of the causes of anemia (hemoglobin, 9.5 g/dL) and thrombocytopenia (platelets, 9.2 x 10(4)/microL), which had been pointed out in a medical checkup half a year previously. A bone marrow examination showed 73% lymphoid cells. Immunophenotyping of these cells were CD19+CD20+CD3-CD5-CD10-CD23-, and light chain restriction (kappa) was positive by fluorescence-activated cell sorting analysis. A computed tomography scan showed mild splenomegaly. To confirm the diagnosis histologically, we performed a splenectomy. Finally, we diagnosed the patient's disease as nonvillous splenic marginal zone lymphoma (SMZL). A month after the splenectomy, the white blood cell count was remarkably increased to 7 x 10(4)/microL with the blastic transformation of lymphoid cells. We first treated the patient with fludarabine and then with the CHOP regimen (cyclophosphamide, hydroxydaunomycin, vincristine [Oncovin], and prednisone), but the disease was so refractory that the patient died of the disease 13 months after the splenectomy. Immunohistochemical staining and a molecular examination for p53 were carried out with specimens from the splenectomy. We found overexpression of the p53 protein in lymphoid cells and a point missense mutation in codon 280 at exon 8 that changed AGA (Arg) to AGT (Ser). This case may indicate the existence of a more aggressive subset of SMZL, suggesting a reconsideration of the roles of splenectomy and p53 overexpression in the diagnostic and therapeutic approaches to patients with SMZL.
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PMID:Blastic transformation after splenectomy in a patient with nonvillous splenic marginal zone lymphoma with p53 overexpression: a case report. 1615 23


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