Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.44 (AGT)
 770 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Limited tryptic digestion of spectrin (Sp) from seven related individuals manifesting hereditary elliptocytosis (HE) or hereditary pyropoikilocytosis (HPP) phenotypes revealed the presence of a novel peptide with a molecular weight of 78 Kd and a concomitant decrease in the alpha I domain (80-Kd peptide), which is the domain involved in the dimer self-association process. Sp from the normal members of this white family exhibited a normal peptide pattern, as compared with controls. The abnormal peptide pattern was associated with a decreased ability of Sp dimer to self-associate. In this kindred in which three generations were available for study, the clinical manifestations were quite variable and ranged from the asymptomatic HE carrier state to hemolytic HE or to severe anemia requiring splenectomy. The severity of the disease appeared to be correlated both with the amount of mutant spectrin (31% to 69%) and with the excess of the Sp dimer found in the membrane (26% to 60%, compared with a normal value of 5.6% +/- 2.2%). Partial amino acid sequencing showed that the alpha I/78-Kd peptide resulted from cleavage at lysine residue 10 of the alpha I/80-Kd domain. Knowledge of the exon/intron structure of cloned genomic DNA encoding the alpha I domain allowed us to amplify in vitro a DNA fragment containing the third exon of the alpha-spectrin gene. The amplified fragment was subcloned and sequenced. A G to T transversion was found in the 39th codon (AGT for AGG), which changed the normal arginine to a serine. Hybridization of amplified DNAs with allele-specific oligonucleotides corresponding to the normal and mutant sequences confirmed the presence of the mutation in three other HE members of the family (the propositus mother, brother, and sister).
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PMID:Sp alpha I/78: a mutation of the alpha I spectrin domain in a white kindred with HE and HPP phenotypes. 256 62

We investigated the genetic defects in two patients with familial lecithin:cholesterol acyltransferase (LCAT) deficiency. Their clinical manifestations including corneal opacities, anemia, proteinuria, and hypoalphalipoproteinemia were identical for familial LCAT deficiency. Their LCAT activities and the cholesterol esterification rate (CER) were nearly zero, and their LCAT masses were below 10% of normal control values. Sequence analysis of the amplified DNA of case 1 revealed one base deletion of G at base 873 (first position of Val264) in exon 6, leading to a premature termination by frameshift. Sequence analysis of amplified DNA of case 2 revealed a single G to A converting Gly (GGT) to Ser (AGT) substitution at residue 344. When COS-1 cells were transfected with these mutants, LCAT activity in the medium was nearly zero, and the LCAT mass was undetectable (< 0.01 microgram/ml). In contrast, LCAT activity in the medium of COS-1 cells, transfected with wild-type LCAT, was 1.7 nmol/h per ml and the LCAT mass was 0.09 micrograms/ml. The LCAT mass in the cell lysates of the mutants was less than 12% of control for case 1 and 18% of control for case 2. Northern blot analysis of the mRNA of COS-1 cells transfected with the mutants showed the same amounts of LCAT mRNA as compared with wild-type LCAT. Biosynthesis of mutant LCATs was analyzed by pulse-chase and immunocytochemistry in transfected baby hamster kidney cells. SDS-PAGE/fluorography demonstrated that wild-type LCAT was synthesized as a high-mannose type of 56 kDa, which was very slowly converted to a mature form of 67 kDa and was secreted into the media. In contrast to the wild-type LCAT, the mutant precursors were not processed into the mature form but slowly degraded along with chase times. On steady and continuous labeling in the case of wild-type LCAT, the mature 67 kDa form was observed in both the cell lysate and media, whereas no mature form was detected in the cell lysates and media which were transfected mutant LCATs. These data suggest that the mutant LCATs are actually synthesized in an amount comparable to that of wild-type, but they are slowly degraded without being processed into the mature form. The immunocytochemistry revealed that mutant LCATs were mainly retained in the endoplasmic reticulum. These data suggest that these two mutations may disrupt the mutant LCATs' transport from the endoplasmic reticulum into Golgi apparatus, resulting in LCAT deficiency.
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PMID:Two novel point mutations in the lecithin:cholesterol acyltransferase (LCAT) gene resulting in LCAT deficiency: LCAT (G873 deletion) and LCAT (Gly344-->Ser). 865 71

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

Theileriosis is an economically important haemoprotozoal disease with high morbidity and mortality in cattle. Buparvaquone is very effective in the treatment of Theileria infections in cattle. The present study reported an outbreak of bovine tropical theileriosis in Fars Province, southern Iran with buparvaquone treatment failure associated with mutations in drug-binding sites of its causative agent. The infected animals (n=8) exhibited poor condition, fever, anemia, rough coat and superficial lymph node enlargement. Both blood smears and lymph nodes punctures were positive and further molecular examination revealed that these animals were infected with Theileria annulata. Death occurred in seven of the eight infected animals in spite of the buparvaquone treatment. At molecular study, two types of important single-base mutations were observed in the cytochrome b gene of the parasite. These changes resulted in amino acid mutations in the parasite cytochrome b from serine (AGT) 109 to glycine (GGT) for the six dead cases and proline (CCT) 233 to serine (TCT) for one dead case within strongly Q(o) drug-binding sites. In contrast, neither of these mutations was found in the parasite cytochrome b for the buvarvaquone-treated animal. It seems that these mutation sites are associated with resistance to buparvaquone, a hydroxynaphthoquinone compound.
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PMID:Point mutations in the Theileria annulata cytochrome b gene is associated with buparvaquone treatment failure. 2230 56