Abstract:
OBJECTIVE:Heterozygous inactivating mutations of the calcium-sensing receptor (CaR) gene cause familial hypocalciuric hypercalcaemia (FHH), a generally benign disorder characterized by mild to moderate PTH-dependent hypercalcaemia. We aimed to identify the causative CaR mutations in three families with FHH and examine the correlation between type of mutation and biochemical and/or functional phenotypes. PATIENTS, DESIGN AND MEASUREMENTS: The CaR gene from FHH family members was assessed for mutations by direct DNA sequencing and mutations were confirmed by restriction enzyme analysis. Functional studies on two missense mutations were conducted by introducing them by site-directed mutagenesis into the CaR cloned into a mammalian expression vector, and assessing calcium responsiveness using an inositol phosphate (IP) assay in HEK293 cells. Biochemical data from patients heterozygous for each type of mutant were correlated with functionality. RESULTS:Two novel nonsense mutations (R25stop and K323stop) and one novel missense mutation (G778D) were identified. The G778D mutant receptor and another mutation identified in an earlier study (L174R) demonstrated a complete lack of Ca2+ responsiveness using the IP assay. When cotransfected with wild-type receptor, the mutant receptors demonstrated a dominant-negative effect on wild-type receptor response, with L174R having a more pronounced effect than G778D. Significantly more severe hypercalcaemia and a trend towards higher PTH levels were observed in patients heterozygous for CaR mutants with a stronger dominant-negative effect. CONCLUSIONS:Naturally occurring CaR mutations with differences in dominant-negative effect on wild-type receptor demonstrate differences in biochemical severity in FHH.
journal_name
Clin Endocrinol (Oxf)journal_title
Clinical endocrinologyauthors
Ward BK,Magno AL,Blitvich BJ,Rea AJ,Stuckey BG,Walsh JP,Ratajczak Tdoi
10.1111/j.1365-2265.2006.02512.xsubject
Has Abstractpub_date
2006-05-01 00:00:00pages
580-7issue
5eissn
0300-0664issn
1365-2265pii
CEN2512journal_volume
64pub_type
杂志文章abstract:OBJECTIVE:We have investigated plasma potassium changes during insulin-induced hypoglycaemia (IIH) in adult patients with growth hormone deficiency (GHD) who have low total body potassium and may also have a vulnerable myocardium due to an increased prevalence of atherosclerosis. DESIGN:Hypoglycaemia was induced throu...
journal_title:Clinical endocrinology
pub_type: 杂志文章
doi:10.1046/j.1365-2265.1998.00508.x
更新日期:1998-08-01 00:00:00
abstract::The role of bromocriptine in the treatment of non-functioning pituitary tumours is not yet defined. Patients with these tumours who present with visual field defects usually undergo immediate surgery. Three consecutive patients are reported: each had rapid improvement in their visual field defects following bromocript...
journal_title:Clinical endocrinology
pub_type: 杂志文章
doi:10.1111/j.1365-2265.1986.tb03625.x
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journal_title:Clinical endocrinology
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journal_title:Clinical endocrinology
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abstract::The ultrastructural effects of a Leydig cell tumour of the testis on nontumorous testicular tissue have not yet been reported. Described here are the electron microscopic findings in the nonneoplastic testicular tissue of a patient with a feminizing testicular Leydig cell neoplasm. Serial studies were carried out over...
journal_title:Clinical endocrinology
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doi:10.1111/j.1365-2265.1977.tb02003.x
更新日期:1977-02-01 00:00:00
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journal_title:Clinical endocrinology
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journal_title:Clinical endocrinology
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doi:10.1111/j.1365-2265.2005.02368.x
更新日期:2005-11-01 00:00:00
abstract:OBJECTIVE:Recent studies have shown that Graves' disease (GD) is linked to and associated with alleles of the cytotoxic T lymphocyte antigen-4 (CTLA4) locus. However, the true pathogenic polymorphism(s) at this locus remains uncertain. Moreover, the association studies of the promoter CTLA4(-318)C/T polymorphism in whi...
journal_title:Clinical endocrinology
pub_type: 杂志文章
doi:10.1046/j.1365-2265.2003.01778.x
更新日期:2003-06-01 00:00:00
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journal_title:Clinical endocrinology
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更新日期:2005-12-01 00:00:00
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journal_title:Clinical endocrinology
pub_type: 杂志文章
doi:10.1111/j.1365-2265.1985.tb00152.x
更新日期:1985-04-01 00:00:00
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journal_title:Clinical endocrinology
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更新日期:1975-03-01 00:00:00
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journal_title:Clinical endocrinology
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更新日期:1988-08-01 00:00:00
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更新日期:1991-12-01 00:00:00
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journal_title:Clinical endocrinology
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doi:10.1046/j.1365-2265.2003.01633.x
更新日期:2003-01-01 00:00:00
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journal_title:Clinical endocrinology
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更新日期:2011-12-01 00:00:00
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更新日期:2008-12-01 00:00:00
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journal_title:Clinical endocrinology
pub_type: 临床试验,杂志文章,随机对照试验
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更新日期:1989-06-01 00:00:00
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journal_title:Clinical endocrinology
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更新日期:2016-03-01 00:00:00
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journal_title:Clinical endocrinology
pub_type: 杂志文章
doi:10.1111/j.1365-2265.1994.tb03782.x
更新日期:1994-07-01 00:00:00
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journal_title:Clinical endocrinology
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更新日期:2012-12-01 00:00:00
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journal_title:Clinical endocrinology
pub_type: 杂志文章
doi:
更新日期:1976-01-01 00:00:00
abstract::To test whether the administration of sodium fluoride in vivo results in an increase in osteocalcin concentration, we administered sodium fluoride to seven healthy male subjects for a period of 3 weeks. Fasting calcium, phosphate, alkaline phosphatase, 25-hydroxyvitamin D, parathyroid hormone and osteocalcin were meas...
journal_title:Clinical endocrinology
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doi:10.1111/j.1365-2265.1988.tb02893.x
更新日期:1988-10-01 00:00:00
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journal_title:Clinical endocrinology
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doi:10.1111/j.1365-2265.1994.tb02453.x
更新日期:1994-01-01 00:00:00
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journal_title:Clinical endocrinology
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doi:10.1111/j.1365-2265.1989.tb00264.x
更新日期:1989-06-01 00:00:00
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更新日期:2015-12-01 00:00:00
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journal_title:Clinical endocrinology
pub_type: 杂志文章
doi:10.1111/j.1365-2265.1994.tb02442.x
更新日期:1994-01-01 00:00:00
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更新日期:2016-02-01 00:00:00
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更新日期:2015-10-01 00:00:00