Identification and characterization of D410E, a novel mutation in the loop 3 domain of CASR, in autosomal dominant hypocalcemia and a therapeutic approach using a novel calcilytic, AXT914. (10th April 2013)

• Record Type: Journal Article
• Authors: Park, So Young; Mun, Hee‐Chang; Eom, Young Sil; Baek, Hae Lim; Jung, Tae Sik; Kim, Chul Hoon; Hong, Suntaek; Lee, Sihoon
• Is Part Of: Clinical endocrinology. Volume 78:Number 5(2013:May)
• Page Start: 687
• Page End: 693
• Publication Date: 2013-04-10
• Subjects: Endocrinology -- Periodicals; 616.4005
• DOI: 10.1111/cen.12056
• Languages: English
• ISSNs: 0300-0664

Abstract

<abstract abstract-type="main" id="cen12056-abs-0001"> <title>Summary</title> <sec id="cen12056-sec-0001" sec-type="section"> <title>Objective</title> <p>Activating mutations of the calcium‐sensing receptor (<italic>CASR</italic>) gene are associated with autosomal dominant hypocalcemia (ADH) characterized by benign hypocalcemia, inappropriately low (PTH) levels and mostly hypercalciuria. Herein, we report a novel activating mutation in the <italic>CASR</italic> gene in a Korean family with ADH.</p> </sec> <sec id="cen12056-sec-0002" sec-type="section"> <title>Method</title> <p>The <italic>CASR</italic> gene was sequenced in the patient with ADH. The identified mutations were also evaluated in the patient's family members by PCR‐based sequencing. For functional studies, we examined phosphorylation of ERK1/2. In addition, intracellular Ca<sup>2+</sup> mobilization and the effects of the calcilytic, AXT914 were measured using fluorophore Fura‐2 dye.</p> </sec> <sec id="cen12056-sec-0003" sec-type="section"> <title>Result</title> <p>Direct sequencing analysis of the <italic>CASR</italic> gene showed that the proband and her daughter possess a novel mutation c.1230T>A, resulting in a D410E missense mutation on exon 4 of the <italic>CASR</italic> gene. Escalation of the extracellular Ca<sup>2+</sup> concentration resulted in stronger phosphorylation of ERK1/2 and higher levels of intracellular Ca<sup>2+</sup> in HEK293 cells expressing mutant CASR, compared with wild‐type CASR. The increase in intracellular Ca<sup>2+</sup> signalling via CASR was successively blunted by treatment with AXT914.</p> </sec> <sec id="cen12056-sec-0004" sec-type="section"> <title>Conclusions</title> <p>Over 60 activating mutations in the <italic>CASR</italic> gene have been identified to cause ADH so far. Here, we add one more activating mutation that causes ADH. The novel activating mutation (D410E) occurred in the loop 3 region of CASR, where its function was believed to be of little importance; therefore, this mutation may be of interest. Further clinical study will be needed to validate the effectiveness of calcilytics in treatment of ADH <italic>in vivo</italic>.</p> </sec> </abstract>