Dataset Information

Identification of a novel large CASR deletion in a patient with familial hypocalciuric hypercalcemia.

ABSTRACT: Familial hypocalciuric hypercalcemia type I is an autosomal dominant disorder caused by heterozygous loss-of-function mutations in the CASR gene and is characterized by moderately elevated serum calcium concentrations, low urinary calcium excretion and inappropriately normal or mildly elevated parathyroid hormone (PTH) concentrations. We performed a clinical and genetic characterization of one patient suspected of familial hypocalciuric hypercalcemia type I. Patient presented persistent hypercalcemia with normal PTH and 25-hydroxyvitamin D levels. The CASR was screened for mutations by PCR followed by direct Sanger sequencing and, in order to detect large deletions or duplications, multiplex ligation-dependent probe amplification (MLPA) was used. One large deletion of 973 nucleotides in heterozygous state (c.1733-255_2450del) was detected. This is the first large deletion detected by the MLPA technique in the CASR gene. Learning points: Molecular studies are important to confirm the differential diagnosis of FHH from primary hyperparathyroidism. Large deletions or duplications in the CASR gene can be detected by the MLPA technique. Understanding the functional impact of the mutations is critical for leading pharmacological research and could facilitate the therapy of patients.

SUBMITTER: Garcia-Castano A

PROVIDER: S-EPMC6280130 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Identification of a novel large CASR deletion in a patient with familial hypocalciuric hypercalcemia.

García-Castaño Alejandro A Madariaga Leire L Azriel Sharona S Pérez de Nanclares Gustavo G Martínez de LaPiscina Idoia I Martínez Rosa R Urrutia Inés I Aguayo Aníbal A Gaztambide Sonia S Castaño Luis L

Endocrinology, diabetes & metabolism case reports 20181205

Familial hypocalciuric hypercalcemia type I is an autosomal dominant disorder caused by heterozygous loss-of-function mutations in the CASR gene and is characterized by moderately elevated serum calcium concentrations, low urinary calcium excretion and inappropriately normal or mildly elevated parathyroid hormone (PTH) concentrations. We performed a clinical and genetic characterization of one patient suspected of familial hypocalciuric hypercalcemia type I. Patient presented persistent hypercal ...[more]

PMID: 30530875

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Project description:G-protein subunit ?-11 (G?11 ) couples the calcium-sensing receptor (CaSR) to phospholipase C (PLC)-mediated intracellular calcium (Ca2+i ) and mitogen-activated protein kinase (MAPK) signaling, which in the parathyroid glands and kidneys regulates parathyroid hormone release and urinary calcium excretion, respectively. Heterozygous germline loss-of-function G?11 mutations cause familial hypocalciuric hypercalcemia type 2 (FHH2), for which effective therapies are currently not available. Here, we report a novel heterozygous G?11 germline mutation, Phe220Ser, which was associated with hypercalcemia in a family with FHH2. Homology modeling showed the wild-type (WT) Phe220 nonpolar residue to form part of a cluster of hydrophobic residues within a highly conserved cleft region of G?11 , which binds to and activates PLC; and predicted that substitution of Phe220 with the mutant Ser220 polar hydrophilic residue would disrupt PLC-mediated signaling. In vitro studies involving transient transfection of WT and mutant G?11 proteins into HEK293 cells, which express the CaSR, showed the mutant Ser220 G?11 protein to impair CaSR-mediated Ca2+i and extracellular signal-regulated kinase 1/2 (ERK) MAPK signaling, consistent with diminished activation of PLC. Furthermore, engineered mutagenesis studies demonstrated that loss of hydrophobicity within the G?11 cleft region also impaired signaling by PLC. The loss-of-function associated with the Ser220 G?11 mutant was rectified by treatment of cells with cinacalcet, which is a CaSR-positive allosteric modulator. Furthermore, in vivo administration of cinacalcet to the proband harboring the Phe220Ser G?11 mutation, normalized serum ionized calcium concentrations. Thus, our studies, which report a novel G?11 germline mutation (Phe220Ser) in a family with FHH2, reveal the importance of the G?11 hydrophobic cleft region for CaSR-mediated activation of PLC, and show that allosteric CaSR modulation can rectify the loss-of-function Phe220Ser mutation and ameliorate the hypercalcemia associated with FHH2. © 2017 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.

Dataset Information

Identification of a novel large CASR deletion in a patient with familial hypocalciuric hypercalcemia.

Publications

Identification of a novel large CASR deletion in a patient with familial hypocalciuric hypercalcemia.

Similar Datasets

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