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Human Molecular Genetics Advance Access published online on May 6, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi176
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received March 3, 2005
Revised April 19, 2005
Accepted April 29, 2005

Article

Impaired Cotranslational Processing of the Calcium-sensing Receptor due to Signal Peptide Missense Mutations in Familial Hypocalciuric Hypercalcemia

Svetlana Pidasheva 1, Lucie Canaff 1, William F. Simonds 2, Stephen J. Marx 2, and Geoffrey N. Hendy 3*

1 Department of Medicine, Royal Victoria Hospital, McGill University, Montreal, QC, Canada; Department of Calcium Research Laboratory, Royal Victoria Hospital, McGill University, Montreal, QC, Canada
2 Department of Metabolic Diseases Branch, NIDDK, NIH, Bethesda, MD, USA
3 Department of Medicine, Royal Victoria Hospital, McGill University, Montreal, QC, Canada; Department of Physiology, Royal Victoria Hospital, McGill University, Montreal, QC, Canada; Department of Human Genetics, Royal Victoria Hospital, McGill University, Montreal, QC, Canada; Department of Calcium Research Laboratory, Royal Victoria Hospital, McGill University, Montreal, QC, Canada; Department of Hormones and Cancer Research Unit, Royal Victoria Hospital, McGill University, Montreal, QC, Canada

* To whom correspondence should be addressed.
Geoffrey N. Hendy, E-mail: geoffrey.hendy{at}mcgill.ca


  Abstract

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 NH2-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, L11S, L13P and T14A, lie within the signal peptide hydrophobic core. When transiently transfected into kidney cells, L11S and L13P mutants demonstrated reduced intracellular and plasma membrane expression and signaling to the MAPK pathway in response to extracellular calcium relative to wild-type CASR and the T14A mutant. All mutant CASR RNAs translated into protein normally. In cotranslational processing assays that test the functionality of the signal peptide in the early secretory pathway, the wild-type CASR and mutant T14A nascent polypeptides were targeted to microsomal vesicles, representing the ER, translocated into the vesicular lumen and underwent core N-glycosylation. In contrast, the L11S and L13P 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 L11S and L13P mutants are markedly impaired with respect to cotranslational processing, accounting for the observed parathyroid dysfunction.


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