Rare Diseases Symptoms Automatic Extraction

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, 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 mitogen-activated protein kinase 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, which 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.

Diseases presenting "first study" symptom

  • achondroplasia
  • acute rheumatic fever
  • alexander disease
  • aniridia
  • coats disease
  • congenital adrenal hyperplasia
  • cowden syndrome
  • dystrophic epidermolysis bullosa
  • erythropoietic protoporphyria
  • familial hypocalciuric hypercalcemia
  • familial mediterranean fever
  • heparin-induced thrombocytopenia
  • hirschsprung disease
  • krabbe disease
  • locked-in syndrome
  • oculocutaneous albinism
  • primary effusion lymphoma
  • waldenström macroglobulinemia
  • wiskott-aldrich syndrome
  • zellweger syndrome

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