Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The calcium-sensing receptor (CASR) is a plasma membrane G protein coupled receptor that is expressed in the parathyroid hormone (PTH) producing chief cells of the parathyroid gland and the cells lining the kidney tubule. By virtue of its ability to sense small changes in circulating calcium concentration ([Ca(2+)](o)) and to couple this information to intracellular signaling pathways that modify PTH secretion or renal cation handling, the CASR plays an essential role in maintaining mineral ion homeostasis. Inherited abnormalities of the CASR gene located on chromosome 3p13.3-21 can cause either hypercalcemia or hypocalcemia depending upon whether they are inactivating or activating, respectively. Heterozygous loss-of-function mutations give rise to familial (benign) hypocalciuric hypercalcemia (FHH) in which the lifelong hypercalcemia is asymptomatic. The homozygous condition manifests itself as neonatal severe hyperparathyroidism (NSHPT), a rare disorder characterized by extreme hypercalcemia and the bony changes of hyperparathyroidism which occur in infancy. The disorder autosomal dominant hypocalcemia (ADH) is due to gain-of-function mutations in the CASR gene. ADH may be asymptomatic or present with neonatal or childhood seizures. A common polymorphism in the intracellular tail of the CASR, Ala to Ser at position 986, has a modest effect on the serum calcium concentration in healthy individuals.
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PMID:Mutations of the calcium-sensing receptor (CASR) in familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia. 1101 39

Autosomal dominant hypocalcemia can be caused by activating mutations of the calcium-sensing receptor (CaSR) gene. We experienced two patients (proband and her daughter) with hypocalcemia caused by a missense mutation of the CaSR gene. The proband, aged 25, showed hypocalcemia and hypoparathyroidism from infancy. She had been diagnosed as having idiopathic hypoparathyroidism and had been treated with calcitriol. She gave birth to a female infant at age 24 years. Her daughter was found to have hypocalcemia (Ca, 6.6mg/dl), without seizure or tetany, when she was 7 months old. DNA analysis of their CaSR genes showed a novel heterozygous mutation at codon 129 (TGC-to-AGC) with substitution of cysteine for serine (C129S). Familial examination revealed that this mutation had occurred de-novo in the proband. Wild-type and niutant (C129S) CaSR cDNA were transfected into HEK293 cells, and intracellular calcium concentrations were measured with a fluorescent calcium indicator. HEK cells transfected with the C129S mutant CaSR gene showed a larger increase in intracellular calcium concentration in response to the change in the extracellular calcium concentration than HEK cells transfected with the wild-type receptor. We conclude that the C129S mutation in the CaSR gene observed in these patients causes autosomal dominant hypocalcemia.
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PMID:A novel activating mutation (C129S) in the calcium-sensing receptor gene in a Japanese family with autosomal dominant hypocalcemia. 1128 19

To date about 20 activating mutations in the calcium-sensing receptor (CaR) gene have been identified to cause autosomal dominant hypocalcemia (ADH) or sporadic hypoparathyroidism. We report a novel activating mutation in the CaR gene in a Japanese family with ADH. The proband, a 15-yr-old boy, and 5 other patients in 3 generations were asymptomatic, except for the proband's grandmother who had a history of seizures. They showed mild hypocalcemia (1.68-1.98 mmol/liter) with normal urinary calcium excretion and low normal serum PTH levels. Their serum magnesium concentrations were below normal in 3 adults and within the normal range in 3 teenagers. There was a significant positive correlation (r = 0.90; P < 0.05) between the serum calcium and magnesium concentrations of 6 affected members. Nucleotide sequencing revealed that the proband had a known polymorphism (Gly(990)Arg) and a novel heterozygous mutation substituting phenylalanine for serine at codon 820 (Ser(820)Phe) in the sixth transmembrane helix of the CaR. In other family members, the Ser(820)Phe mutation cosegregated with hypocalcemia. The mutation was not detected in 50 control subjects. The Gly(990)Arg polymorphism was observed in 8 of 9 family members with or without hypocalcemia and in 36 of 50 controls. The sensitivity of the Ser(820)Phe mutant CaR to calcium was assessed using transiently transfected HEK293 cells and measuring the increases in intracellular Ca(2+) concentrations in response to the changes in extracellular Ca(2+). The concentration-response curve of the mutant receptor was left-shifted, and its EC(50) (2.5 mM) was significantly (P < 0.05) lower than that of the wild-type CaR (3.3 mM). We conclude that the Ser(820)Phe mutation in the CaR caused ADH in this family. The positive correlation between serum calcium and magnesium levels observed in this family may support the concept that renal CaR acts as a magnesium sensor as well as a calcium sensor.
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PMID:A family of autosomal dominant hypocalcemia with a positive correlation between serum calcium and magnesium: identification of a novel gain of function mutation (Ser(820)Phe) in the calcium-sensing receptor. 1205 Feb 33

Gain-of-function mutations of the calcium-sensing receptor (CaR) gene cause autosomal dominant and/or sporadic hypocalcemia with hypercalciuria. Because treatment of the hypocalcemia with vitamin D and/or calcium in patients with such mutations results in increased hypercalciuria, nephrocalcinosis, and renal impairment, its use should be limited to alleviating the symptoms of symptomatic patients. Because thiazide diuretics have been successfully used to treat patients with hypercalciuria and hypoparathyroidism, they are theoretically useful in reducing urine calcium excretion and maintaining serum calcium levels in patients with gain-of-function mutations of the CaR gene. In this study, we report on the clinical course, molecular analysis, and effects of hydrochlorothiazide therapy in two Japanese patients with gain-of-function mutations of the CaR gene. Within a few weeks after birth, they developed generalized tonic seizures due to hypocalcemia (serum calcium values: 1.1 mmol/liter and 1.3 mmol/liter, respectively). Despite treatment with the standard dose of 1,25-dihydroxyvitamin D(3) in one patient and 1alpha-hydroxyvitamin D(3) in the other, acceptable serum calcium levels near the lower limit of normal were not established, and their urinary calcium excretion inappropriately increased. Addition of hydrochlorothiazide (1 mg/kg) reduced their urinary calcium excretion and maintained their serum calcium concentrations near the lower limit of normal, allowing the 1,25-dihydroxyvitamin D(3) and 1alpha-hydroxyvitamin D(3) doses to be reduced, and it alleviated their symptoms. A heterozygous missense mutation was identified in both patients. In one patient, the mutation was A843E in the seventh transmembrane domain of the CaR, and in the other it was L125P in the N-terminal extracellular domain. In vitro transient transfection of their mutant CaR cDNAs into HEK293 cells shifted the concentration-response curve of Ca(2+) to the left. In conclusion, two sporadic cases of hypercalciuric hypocalcemia were due to de novo gain-of-function mutations of the CaR gene. Hydrochlorothiazide with vitamin D(3) successfully reduced the patients' urinary calcium excretion and controlled their serum calcium concentrations and symptoms. Thiazide diuretics are effective in patients with gain-of function mutations of the CaR gene.
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PMID:Hydrochlorothiazide effectively reduces urinary calcium excretion in two Japanese patients with gain-of-function mutations of the calcium-sensing receptor gene. 1210 2

We report a novel activating mutation (E604K) of the calcium-sensing receptor in a family with autosomal dominant hypocalcemia. Whereas all affected individuals exhibited marked hypocalcemia, some cases with untreated hypocalcemia exhibited seizures in infancy, whereas others were largely asymptomatic from birth into adulthood. The missense mutation E604K (G2182A; GenBank accession no. U20759), which affects an amino acid residue in the C terminus of the cysteine-rich domain of the extracellular head, cosegregated with hypocalcemia in all seven individuals for whom DNA was available. Two unaffected, normocalcemic members of the family did not exhibit the mutation. The molecular impact of the mutation on two key components of the signaling response was assessed in HEK-293 cells transiently transfected with cDNA corresponding to either the wild-type calcium-sensing receptor or the E604K mutation derived by site-directed mutagenesis. There was a significant leftward shift in the concentration response curves for the effects of extracellular Ca(2+) on both intracellular Ca(2+) mobilization (determined by aequorin luminescence) and MAPK activity (determined by luciferase expression). The C terminus of the cysteine-rich domain of the extracellular head may normally act to suppress receptor activity in the presence of low extracellular Ca(2+) concentrations.
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PMID:Autosomal dominant hypocalcemia: a novel activating mutation (E604K) in the cysteine-rich domain of the calcium-sensing receptor. 1257 88

Autosomal dominant hypocalcemia (ADH) caused by activating mutations of calcium-sensing receptor (CaSR) is characterized by hypocalcemia with inappropriately low concentration of PTH and relative hypercalciuria. Active vitamin D treatment often leads to nephrolithiasis and renal impairment in patients with ADH. However, differential diagnosis between ADH and idiopathic hypoparathyroidism is sometimes very difficult. Here, we report a mutation of CaSR and its functional property found in three generations of a Japanese family. The proband developed seizures at 7 days of age. His mother and elder sister were discovered to have hypoparathyroidism by family survey, but his father was normocalcemic. His grandfather developed heart failure and was found to have hypoparathyroidism. All affected members had been treated with active vitamin D3 and bilateral nephrolithiasis were detected in three of them. DNA sequencing revealed that all affected patients had a heterozygous mutation in CaSR gene that causes proline to leucine substitution at codon 221 (P221L). In vitro functional analysis of the mutant CaSR by measuring inositol 1,4,5-trisphosphate production in response to changes of extracellular Ca indicated that this mutation is an activating one and responsible for ADH in this family. Therefore, careful monitoring of urinary Ca excretion before and during treatment of PTH-deficient hypoparathyroidism is very important, and screening of CaSR mutation should be considered in patients with relative hypercalciuria or with a family history of hypocalcemia.
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PMID:A family of autosomal dominant hypocalcemia with an activating mutation of calcium-sensing receptor gene. 1273 14

A novel missense activating mutation in the extracellular calcium-sensing receptor (CaSR) is reported in this work. It was identified in three related subjects with the phenotypic features of autosomal dominant hypocalcemia (ADH). The proband, a 27-year-old woman, diagnosed as having hypoparathyroidism at 7 years of age and a history of seizures, showed the highest penetrance of the mutation. The remaining two affected members presented asymptomatic chronic hypocalcemia despite severe hypoparathyroidism associated with high levels of serum phosphate and calcium urinary excretion. The missense mutation (Glu(604)Lys) affected an amino acid residue in the C terminus of the cysteine-rich domain of the extracellular amino-terminal domain, which seems to be required for the coupling of ligand binding to the activation of intracellular signaling pathways. This genetic change cosegregated with hypocalcemia in all the individuals where the mutation was found. As parathyroid hormone (PTH) secretion is the regulatory target of the CaSR, polymorphism analysis of the PTH gene was carried out. PTH polymorphisms were analyzed in the kindred studied. Affected members for the Glu(604)Lys CaSR mutation which also carried the uncommon PTH alleles showed higher penetrance of the mutation, with more severe autosomal dominant hypocalcemia. These results suggested that the PTH gene could act as a modifier locus of ADH, affecting the penetrance of the activating CaSR mutation described.
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PMID:A novel mutation in the calcium-sensing receptor responsible for autosomal dominant hypocalcemia in a family with two uncommon parathyroid hormone polymorphisms. 1451 94

Familial hypocalciuric hypercalcemia (FHH) is caused by heterozygous loss-of-function mutations in the calcium-sensing receptor (CASR), in which the lifelong hypercalcemia is generally asymptomatic. Homozygous loss-of-function CASR mutations manifest as neonatal severe hyperparathyroidism (NSHPT), a rare disorder characterized by extreme hypercalcemia and the bony changes of hyperparathyroidism, which occur in infancy. Activating mutations in the CASR gene have been identified in several families with autosomal dominant hypocalcemia (ADH), autosomal dominant hypoparathyroidism, or hypocalcemic hypercalciuria. Individuals with ADH may have mild hypocalcemia and relatively few symptoms. However, in some cases seizures can occur, especially in younger patients, and these often happen during febrile episodes due to intercurrent infection. Thus far, 112 naturally-occurring mutations in the human CASR gene have been reported, of which 80 are unique and 32 are recurrent. To better understand the mutations causing defects in the CASR gene and to define specific regions relevant for ligand-receptor interaction and other receptor functions, the data on mutations were collected and the information was centralized in the CASRdb (www.casrdb.mcgill.ca), which is easily and quickly accessible by search engines for retrieval of specific information. The information can be searched by mutation, genotype-phenotype, clinical data, in vitro analyses, and authors of publications describing the mutations. CASRdb is regularly updated for new mutations and it also provides a mutation submission form to ensure up-to-date information. The home page of this database provides links to different web pages that are relevant to the CASR, as well as disease clinical pages, sequence of the CASR gene exons, and position of mutations in the CASR. The CASRdb will help researchers to better understand and analyze the mutations, and aid in structure-function analyses.
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PMID:CASRdb: calcium-sensing receptor locus-specific database for mutations causing familial (benign) hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia. 1524 91

Mutations in the calcium-sensing receptor gene (CaSR) may result in disorders of calcium homeostasis manifesting as familial benign hypocalciuric hypercalcaemia (FBHH), neonatal severe hyperparathyroidism (NSHPT) or autosomal dominant hypocalcaemia with hypercalciuria (ADHH). FBHH may have a population prevalence as high as one in 16 000, and ADHH one in 70 000. NSHPT is very rare. The FBHH condition is usually asymptomatic. Parathyroidectomy does not result in normal serum calcium, and no active treatment is indicated. To differentiate FBHH from primary hyperparathyroidism (PHPT), a guideline which includes measurement of serum calcium, intact parathyroid hormone (PTH), magnesium and fasting urinary calcium excretion is proposed. Screening of family members for hypercalcaemia, and occasionally a search for mutations in the CaSR gene, may be required. The NSHPT condition may manifest with hypercalcaemia, (usually) very elevated serum PTH concentration, subperiosteal erosions and fractures. Milder cases may be managed medically, but respiratory failure, extreme hypercalcaemia and failure to thrive are indications for early parathyroidectomy. The ADHH condition may result in asymptomatic hypocalcaemia, but some affected family members have minor symptoms, and a minority experience seizures in infancy which can recur into adulthood. A significant proportion of cases previously reported as idiopathic hypoparathyroidism (IHP) may in fact be due to mutations in the CaSR gene. In a moderately hypocalcaemic patient with no other clearly discernible cause, an elevated urine calcium:creatinine ratio is suggestive of ADHH, as is the presence of a first-degree relative with hypocalcaemia. If treatment with vitamin D analogues is undertaken, serum and urine calcium should be monitored, advice which applies equally to ADHH and IHP.
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PMID:Clinical and laboratory features of calcium-sensing receptor disorders: a systematic review. 1558 33

Genetic variation in G protein-coupled receptors (GPCRs) results in the disruption of GPCR function in a wide variety of human genetic diseases. In vitro strategies have been used to elucidate the molecular pathologies that underlie naturally occurring GPCR mutations. Various degrees of inactive, overactive, or constitutively active receptors have been identified. These mutations often alter ligand binding, G protein coupling, receptor desensitization, and receptor recycling. The role of inactivating and activating calcium-sensing receptor (CASR) mutations is discussed with respect to familial hypocalciuric hypercalemia (FHH) and autosomal dominant hypocalemia (ADH). Among ADH mutations, those associated with tonic-clonic seizures are discussed. Other receptors discussed include rhodopsin, thyrotropin, parathyroid hormone, melanocortin, follicle-stimulating hormone, luteinizing hormone, gonadotropin-releasing hormone (GnRHR), adrenocorticotropic hormone, vasopressin, endothelin-beta, purinergic, and the G protein associated with asthma (GPRA). Diseases caused by mutations that disrupt GPCR function are significant because they might be selectively targeted by drugs that rescue altered receptors. Examples of drug development based on targeting GPCRs mutated in disease include the calcimimetics used to compensate for some CASR mutations, obesity therapeutics targeting melanocortin receptors, interventions that alter GnRHR loss from the cell surface in idiopathic hypogonadotropic hypogonadism and novel drugs that might rescue the P2RY12 receptor in a rare bleeding disorder. The discovery of GPRA suggests that drug screens against variant GPCRs may identify novel drugs. This review of the variety of GPCRs that are disrupted in monogenic disease provides the basis for examining the significance of common pharmacogenetic variants.
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PMID:G protein-coupled receptors disrupted in human genetic disease. 1837 Feb 33


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