Identification and functional analysis of novel calcium-sensing receptor gene mutation in familial hypocalciuric hypercalcemia

Endocrine Journal

So Nagai³  Hideaki Miyoshi³  Takao Koike³  Narihito Yoshioka³  Takuma Kondo³  Chikara Shimizu²  Toshihiro Tajima¹  Kazuhiro Nanjo³ 

[1] Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan;Department of Laboratory and Transfusion Medicine, Hokkaido University Hospital, Sapporo, Japan;Department of Medicine II, Hokkaido University Graduate School of Medicine, Sapporo, Japan

关键词: Calcium-sensing receptor;    Familial hypocalciuric hypercalcemia;    MAPK signaling pathway;   

DOI  :  10.1507/endocrj.K10E-178

学科分类：内分泌与代谢学

来源: Japan Endocrine Society

【 摘 要 】

References(18)Cited-By(2)Familial hypocalciuric hypercalcemia (FHH) is a benign disorder with heterozygous inactivating mutations in the calcium-sensing receptor (CASR) gene. The present study describes the identification and functional analysis of a novel CASR gene mutation leading to FHH. The proband is a 33-yr-old woman (Ca 11.0 mg/dL, intact-PTH 68 pg/mL, FECa 0.17 %). Leukocyte DNA was isolated in four family members and a novel heterozygous mutation (D190G, GAT>GGT) in exon 4 of CASR gene was identified by direct sequence analysis. The mutant CASR expression vector was constructed by mutagenesis procedure and its response to Ca2+ was characterized by transient transfection into human embryonic kidney (HEK) 293 cells and treatment with increasing extracellular Ca2+ concentrations. HEK cells didn't activate intracellular signaling (MAPK activation) in response to increases of extracellular Ca2+ concentrations when the mutant receptor was expressed normally at the cell surface. The novel heterozygous mutation (D190G) identified in the present study showed that the reduction of activity of CASR to extracellular Ca2+ caused FHH in patients and our study demonstrated the importance of Asp-190 participated in response to Ca2+ in CASR.

【 授权许可】

Unknown