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: UMLS:C0020437 (hypercalcemia)
10,293 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A rare case of ovarian small cell carcinoma is reported. Laboratory examination of a 46-year-old woman with a lower abdominal tumor showed marked hypercalcemia. Her condition deteriorated progressively, and she died one month after admission. A right ovarian tumor, 8 cm in diameter, metastases to multiple organs, and intraperitoneal bleeding were confirmed by autopsy. Microscopically, the small tumor cell had rounded nuclei with small distinct nucleoli and a scanty cytoplasm. Small cell carcinoma was diagnosed from these histological features and the clinical course associated with hypercalcemia. Immunohistochemical studies showed positive staining of neuron specific enolase (NSE) and keratin. Genetic analysis using DNA extracted from paraffin sections of metastatic lesions revealed mutation of K-ras codon 12. Loss of heterozygosity of the p53 and adenomatous polyposis coli (APC) genes was not informative. Previous reports have shown that ras gene mutations occur in 30% of epithelial ovarian tumors and significantly more frequently in mucinous than in other types of ovarian tumors. These results suggest that small cell carcinoma is of epithelial origin and may have a genetic alteration similar to that of mucinous tumors.
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PMID:Ovarian small cell carcinoma with K-ras mutation: a case report with genetic analysis. 854 15

The PTH/PTHrP receptor belongs to a novel family of G-protein-coupled receptors which also includes an insect receptor for a diuretic hormone and the protein encoded by a genomic DNA clone from Caenorhabditis elegans. Despite significant structural conservation, rat, opossum, and human PTH/PTHrP receptor homologs display distinct functional characteristics when tested with either [Arg2, Tyr34]hPTH(1-34)amide or [Nle8.18, Tyr34]bPTH(7-34)-amide. These PTH analogs, and chimeras between rat/opossum and between rat/human PTH/PTHrP receptors, led to the identification of receptor residues that appear to be involved in ligand/receptor interaction and receptor activation, respectively. The search for mutations in the PTH/PTHrP receptor gene in genomic DNA of patients with pseudohypoparathyroidism type Ib (PHP-Ib) revealed several silent polymorphisms and a missense mutation in the receptor's tail region which did not affect receptor function. Mutations in the PTH/PTHrP receptor are therefore rarely, if at all, responsible for PHP-Ib. A mutation in the PTH/PTHrP receptor is, however, the most likely cause of Jansen-type metaphyseal chondrodysplasia, a rare form of short-limbed dwarfism which is associated with severe hypercalcemia despite normal or low levels of circulating PTH and PTHrP. A missense mutation was identified which causes constitutive, ligand-independent receptor activation, and thus explains the laboratory and the growth-plate abnormalities in affected individuals.
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PMID:Functional properties of the PTH/PTHrP receptor. 857 96

The predominant variety of familial benign hypocalciuric hypercalcemia (FBHH) is FBHH(3q), which is associated with presumed inactivating mutations of the cell surface calcium receptor (CaR) gene on chromosome 3q13.3-q21. We sought mutations of the CaR gene in FBHH by direct sequencing of PCR-amplified genomic DNA from 14 affected families: 8 mapped to 3q13, 1 mapped to chromosome 19p, and 5 unmapped. We sequenced the entire coding region of the gene (exons 2-7) in one or two affected members of each family and found six point mutations that altered one amino acid, cosegregated with hypercalcemia, and were absent in more than 100 unaffected persons. Four mutations were unique (S53P, D215G, S657Y, and P748R), and two had been reported previously (P55L and R185Q). Of four mutant CaR proteins expressed in Xenopus oocytes, three were deficient in extracellular Ca2+-induced signaling. No CaR mutations were found in eight families, including the one mapped to chromosome 19p. Three benign polymorphisms occurred in the COOH-terminal region of the CaR protein in 10%, 15%, and 30% of more than 100 unaffected persons. Thus, FBHH-causing CaR mutations were clustered in the NH2-terminal extracellular and membrane-spanning regions of the receptor protein. We suggest that these are important functional domains, probably for calcium binding and signal transduction, respectively. Finally, mutations in regulatory or intronic regions of the CaR gene may also underlie many cases of FBHH.
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PMID:Clustered inactivating mutations and benign polymorphisms of the calcium receptor gene in familial benign hypocalciuric hypercalcemia suggest receptor functional domains. 863 22

Identification of germline mutations in the RET proto-oncogene predisposing to multiple endocrine neoplasia type IIa (MEN-IIa) has allowed a DNA-based approach to diagnosis and treatment by prophylactic thyroidectomy in children testing genetically positive. Although total thyroidectomy is the accepted operation for C cell disease, the necessity of routine total parathyroidectomy and autotransplantation as previously described in these asymptomatic children is questionable, particularly given the low occurrence of hyperparathyroidism in MEN-IIa (10-20%). Thirty-six children (ages 1 month to 12 years) from four MEN-IIa kindreds at risk for disease underwent genetic testing. Mutational analysis was done using a highly sensitive PCR-based denaturing gradient gel electrophoresis technique. Parathyroid or serum calcium concentrations were determined preoperatively. Of the 36 children at risk, 18 were found to have a MEN-IIa mutation; 11 have undergone prophylactic thyroidectomy at ages ranging from 2 to 12 years (mean 7.5 years). In each case, there was no biochemical evidence of hypercalcemia preoperatively, and all parathyroid glands were identified and were found to be grossly normal at exploration. Glands were carefully dissected and left in situ. Postoperatively, 10 of the 11 children maintained normocalcemia, allowing discharge within 24 to 36 hours. Resected thyroid glands contained C cell hyperplasia in nine, medullary carcinoma in one, and normal histology in one. We conclude that an alternative to routine parathyroidectomy may be desirable for prophylactic treatment of MEN-IIa. In situ parathyroid preservation can be safely achieved without compromising the completeness of the thyroid resection. This conservative approach obviates the potential morbidity associated with total parathyroidectomy and autotransplantation.
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PMID:Prophylactic surgery for multiple endocrine neoplasia type IIa after genetic diagnosis: is parathyroid transplantation indicated? 867 56

Williams syndrome (WS) is a multisystem developmental disorder caused by the deletion of contiguous genes at 7q11.23. Hemizygosity of the elastin (ELN) gene can account for the vascular and connective tissue abnormalities observed in WS patients, but the genes that contribute to features such as infantile hypercalcemia, dysmorphic facies, and mental retardation remain to be identified. In addition, the size of the genomic interval commonly deleted in WS patients has not been established. In this study we report the characterization of a 500-kb region that was determined to be deleted in our collection of WS patients. A detailed physical map consisting of cosmid, P1 artificial chromosomes, and yeast artificial chromosomes was constructed and used for gene isolation experiments. Using the techniques of direct cDNA selection and genomic DNA sequencing, three known genes (ELN, LIMK1, and RFC2), a novel gene (WSCR1) with homology to RNA-binding proteins, a gene with homology to restin, and four other putative transcription units were identified. LIMK1 is a protein kinase with two repeats of the LIM/double zinc finger motif, and it is highly expressed in brain. RFC2 is the 40-kDa ATP-binding subunit of replication factor C, which is known to play a role in the elongation of DNA catalyzed by DNA polymerase delta and epsilon. LIMK1 and WSCR1 may be particularly relevant when explaining cognitive defects observed in WS patients.
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PMID:Identification of genes from a 500-kb region at 7q11.23 that is commonly deleted in Williams syndrome patients. 881 60

The parathyroid hormone/parathyroid hormone-related peptide receptor belongs to a distinct family of G protein-coupled receptors, the members of which usually signal through at least two second messenger systems, adenylate cyclase and phospholipase C. The parathyroid hormone/ parathyroid hormone-related peptide receptor is most abundantly expressed in bone, kidney and growth-plate chondrocytes, and, at lower levels, in a variety of fetal and adult tissues. To search for human diseases that are caused by parathyroid hormone/parathyroid hormone-related peptide receptor defects, genomic DNA of patients with pseudohypoparathyroidism type Ib and of patients with Jansen's metaphyseal chondrodysplasia was screened for mutations in all coding exons of the receptor gene. Inactivating parathyroid hormone/parathyroid hormone-related peptide receptor mutations were excluded in patients with pseudohypoparathyroidism type Ib. However, a receptor mutation that causes agonist-independent, constitutive cAMP accumulation was identified in a patient with Jansen's metaphyseal chondrodysplasia, a rare form of short-limbed dwarfism associated with hypercalcemia despite normal or low concentrations of parathyroid hormone and parathyroid hormone-related peptide. These findings allow the conclusion to be drawn that parathyroid hormone/parathyroid hormone-related peptide receptors mediate the endocrine actions of parathyroid hormone, which are required for the control of calcium homeostasis and the autocrine-paracrine actions of parathyroid hormone-related peptide, which are required for normal growth-plate development.
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PMID:Receptors for parathyroid hormone and parathyroid hormone-related peptide: from molecular cloning to definition of diseases. 882 26

Ectopic tumoral production of intact parathyroid hormone (PTH) is rare. The PTH-related protein is the common cause of hypercalcemia in most solid tumors, particularly squamous and renal carcinomas. We report the case of a 71-yr-old man with a PTH-producing squamous cell lung carcinoma. Immunocytochemical analysis of the tumor tissue as well as of cultured tumor cells revealed PTH positive staining. Cultured tumor cells released PTH and were calcium sensitive, producing 122 +/- 16 pg/microgram DNA of intact PTH (mean +/- SEM) at 0.5 mmol/L calcium compared with 26 +/- 2 pg/microgram DNA at 3.0 mmol/L calcium. Somatostatin analogues have been used in the treatment of humoral hypercalcemia of malignancy (HHM). However, we found that somatostatin (0.1 microgram/L) in cultured tumor cells increased the release of intact PTH (123 +/- 19 versus 82 +/- 1 pg/microgram DNA, P < 0.05) and thus might have a negative effect on the HHM. This report is the first to describe a true ectopic PTH-producing squamous cell lung carcinoma associated with HHM.
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PMID:Ectopic production of intact parathyroid hormone by a squamous cell lung carcinoma in vivo and in vitro. 885 39

A missense mutation in the Ca(2+)-sensing receptor (CaSR) gene was previously identified in a Japanese family with familial hypocalciuric hypercalcemia. Five members of this family with the mutation in the CaSR gene also showed abnormal glucose tolerance, whereas family members homozygous for the wildtype CaSR gene were normal in this respect. The potential relation between mutations in the CaSR gene and the incidence of diabetes mellitus was therefore investigated in 27 non-insulin dependent diabetic and 40 normal Japanese subjects. Each exon of the CaSR gene was amplified by the polymerase chain reaction and subjected to single-strand conformation polymorphism (SSCP) analysis. The region of the gene containing the sixth exon showed three distinct patterns on SSCP analysis in both diabetic patients and normal subjects. Direct sequencing of DNA revealed a T/C polymorphism in the fifth intron. The TT genotype was apparent in 59.3% of diabetic patients and in 45.0% of normal subjects. The CC genotype was present in 25.9% of diabetics and in 22.5% of normal subjects. The diabetic patients were divided into three groups on the basis of genotype for the polymorphism (TT, TC, or CC). However, there was no significant difference among the three groups with regard to the method of therapy, the incidence or severity of diabetic complications, duration or family history of disease, HbA1c level, or laboratory data. The polymorphism in the fifth intron of the CaSR gene does not therefore appear to be associated with non-insulin dependent diabetes mellitus.
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PMID:Polymorphism of the human Ca(2+)-sensing receptor gene in Japanese individuals: no relation to non-insulin dependent diabetes mellitus. 893 12

Williams syndrome (WS) is associated with a submicroscopic deletion of the elastin gene (ELN) at 7q11.23. The deletion encompasses closely linked DNA markers. We have investigated 44 patients referred for possible WS using fluorescence in situ hybridization (FISH) analysis with a P1 clone containing an insert from the ELN, as well as performing genotype analysis of patients and parents with four DNA polymorphisms. Twenty-four patients were found to have deletions, 19 of whom were found clinically to have typical WS. The facial features were especially characteristic. None of the patients without detectable deletions was reported to have typical WS features, although one had supravalvular aortic stenosis, hypercalcemia, and mental retardation. No evidence was found in this material for variability of the size of the deletion. Our study supports the usefulness of analysis of ELN deletion in WS patients, both for confirmation of diagnosis and for genetic counselling.
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PMID:Investigation of deletions at 7q11.23 in 44 patients referred for Williams-Beuren syndrome, using FISH and four DNA polymorphisms. 900 95

We examined human T-lymphotropic virus type I (HTLV-I) DNA integration in 68 patients with adult T-cell leukemia/ lymphoma (ATL) by Southern blotting using EcoRI, which does not cut within the 9 kb of the genome and probes for pX and gag-pol region of HTLV-I. We detected defective proviral integration as a monoclonal band of various sizes with the pX but not with the gag-pol probe, or a monoclonal band of less than 9 kb with the pX probe, in 20 patients (29.4%). These were designated defective (D) type. With both probes, a single band greater than 9 kb was detected in 34 (50.0%), designated complete (C) type, and two or more bands greater than 9 kb, were designated multiple (M) type, in 14 (20.6%). Advanced age, a high LDH value, and hypercalcemia were more frequent in D type patients. The median survival time (MST) was 6.8, 24.4, and 33.3 months, for D, C, and M types, respectively (log rank P = .006). Among 52 sequentially examined patients, the HTLV-I integration patterns changed in 4 (7.5%). In three of these four, the rearrangements of the T-cell receptor (TCR)b gene concomitantly changed, suggesting the appearance of a new ATL clone. Another patient had the same rearrangement of the TCRb gene, indicating clonal evolution. The HTLV-I integration pattern changed at crisis from indolent to aggressive ATL in three patients. These findings suggested that the HTLV-I integration patterns have clinical implications in ATL pathophysiology. In contrast to the clonal evolution characteristic of the multistep carcinogenesis of most human malignancies, the frequent clonal change of ATL at crisis is a peculiar phenomenon, probably reflecting the emergence of multiple premalignant clones in viral leukemogenesis as suggested in Epstein-Barr virus associated lymphomagenesis in the immunocompromised host.
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PMID:Integration patterns of HTLV-I provirus in relation to the clinical course of ATL: frequent clonal change at crisis from indolent disease. 902 26


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