CASR Gene (casr + gene)

Distribution by Scientific Domains
Life Sciences60%

Selected Abstracts

CASRdb: calcium-sensing receptor locus-specific database for mutations causing familial (benign) hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia,

HUMAN MUTATION, Issue 2 2004
Svetlana Pidasheva
Abstract 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. Hum Mutat 24:107,111, 2004. © 2004 Wiley-Liss, Inc. [source]

Attributing Hardy-Weinberg Disequilibrium to Population Stratification and Genetic Association in Case-Control Studies

ANNALS OF HUMAN GENETICS, Issue 1 2010
Vaneeta K. Grover
Summary Loci exhibiting Hardy-Weinberg disequilibrium (HWD) are often excluded from association studies, because HWD may indicate genotyping error, population stratification or selection bias. For case-control studies, HWD can result from a genetic effect at the locus. We extend the modelling to accommodate both stratification and genetic effects. Theoretical genotype frequencies and HWD coefficients are derived under a general genetic model for a population with two strata. Maximum likelihood is used to estimate model parameters and a test for lack of fit identifies the models most consistent with the data. Simulations were used to assess the method. The technique was applied to a group of ethnically and clinically heterogeneous kidney stone formers and controls, both exhibiting HWD for the R990G SNP of the CASR gene. Results indicate the best fitting model incorporates both stratification and genetic association. The ability of our method to apportion HWD to stratification and genetic effects may well be a significant advance in dealing with heterogeneity in case-control genetic association studies. [source]

Genetic analyses in patients with familial isolated hyperparathyroidism and hyperparathyroidism,jaw tumour syndrome

CLINICAL ENDOCRINOLOGY, Issue 1 2006
Noriko Mizusawa
Summary Background, A subset of familial isolated primary hyperparathyroidism (FIHP) is a variant of hyperparathyroidism,jaw tumour syndrome (HPT-JT). Aim/patients and methods, We investigated the involvement of the HRPT2, MEN1 and CASR genes in 11 provisional FIHP families and two HPT-JT families. Results, Germline mutations of HRPT2 were found in two of the 11 FIHP families and one of the two HPT-JT families. One FIHP family with parathyroid carcinoma and atypical adenomas and another FIHP family with cystic parathyroid adenoma had novel frameshift mutations of 518,521del and 62,66del, respectively. In a patient with HPT-JT, a de novo germline mutation of 39delC was detected. Novel somatic HRPT2 mutations of 70,73del and 95,102del were found in two of five parathyroid tumours in a family with a 518,521del mutation. Biallelic inactivation of HRPT2 by a combination of germline and somatic mutation was confirmed in the parathyroid tumours. The finding that two families diagnosed with FIHP carried HRPT2 mutations suggests that they have occult HPT-JT. In the remaining 10 families, one family had a missense MEN1 mutation. No mutations of CASR were detected. Conclusion, Our results confirm the need to test for HRPT2 in FIHP families, especially those with parathyroid carcinomas, atypical adenomas or adenomas with cystic change. [source]

Neonatal severe hyperparathyroidism associated with a novel de novo heterozygous R551K inactivating mutation and a heterozygous A986S polymorphism of the calcium-sensing receptor gene

CLINICAL ENDOCRINOLOGY, Issue 3 2007
Judit Tőke
Summary Introduction, Neonatal severe hyperparathyroidism (NSHPT) is induced by inactivating mutations of human calcium-sensing receptor (CaSR). Only three heterozygous de novo inactivating mutations of CaSR causing NSHPT have been described. We report the case of a now 11-year-old boy with NSHPT and we characterize a novel inactivating mutation along with the results of some functional analyses. Patient and methods, As a neonate the patient presented the clinical syndrome of NSHPT. At 6 years of age persisting hypercalcaemia without clinical symptoms was documented, and the patient remained completely symptom free without parathyroid surgery until his present age of 11 years. The entire coding region of the CaSR gene of the patient and his family members was sequenced. Functional investigation was performed in HEK-293 cells, transiently transfected with wild type and mutant CaSR plasmid constructs. Results, Sequence analysis revealed a novel de novo heterozygous mutation at codon 551 (AGG,AAG), predicting a change of arginine to lysine (R551K) and a known heterozygous polymorphism (A986S) on the same allele, which was inherited from the father. We demonstrated that the novel R551K mutation significantly reduced the calcium sensitivity of CaSR (EC50: from 3·38 ± 0·62,6·10 ± 0·83 mmol/l), which was not alleviated by the simultaneous presence of A986S polymorphism. Conclusions, We present the fourth NSHPT case induced by a novel de novo heterozygous inactivating mutation (R551K) of the CaSR gene. The disease gradually reverted to a symptomless, benign condition resembling familial hypocalciuric hypercalcaemia without any surgical intervention. [source]