Impaired cotranslational processing of the calcium-sensing receptor due to signal peptide missense mutations in familial hypocalciuric hypercalcemia.

[familial hypocalciuric hypercalcemia]

The CASR , a cell surface glycoprotein expressed in parathyroid gland and kidney , is critical for maintaining extracellular calcium homeostasis . The inherited disorders , familial hypocalciuric hypercalcemia (FHH ) and neonatal severe hyperparathyroidism (NSHPT ), are caused by inactivating mutations in the CASR gene . The CASR has an N-terminal , 19 amino acid signal peptide that is predicted to direct the nascent polypeptide chain , as it emerges from the ribosome , into the endoplasmic reticulum (ER ). Here , we report the functional characterization of three CASR mutations identified in hypercalcemic /hyperparathyroid patients . The mutations , L 11 S , L 13 P and T 14 A , lie within the signal peptide hydrophobic core . When transiently transfected into kidney cells , L 11 S and L 13 P mutants demonstrated reduced intracellular and plasma membrane expression and signaling to the mitogen-activated protein kinase pathway in response to extracellular calcium relative to wild-type CASR and the T 14 A mutant . All mutant CASR RNAs translated into protein normally . In cotranslational processing assays , which test the functionality of the signal peptide in the early secretory pathway , the wild-type CASR and mutant T 14 A nascent polypeptides were targeted to microsomal vesicles , representing the ER , translocated into the vesicular lumen and underwent core N-glycosylation . In contrast , the L 11 S and L 13 P mutants failed to be inserted in the microsomes and undergo glycosylation . This is the first study examining the function of the CASR signal sequence and reveals that both L 11 S and L 13 P mutants are markedly impaired with respect to cotranslational processing , accounting for the observed parathyroid dysfunction .

Diseases
Validation

Diseases presenting "calcium homeostasis" symptom

dentin dysplasia

familial hypocalciuric hypercalcemia

inclusion body myositis

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