Rare Diseases Symptoms Automatic Extraction

Calcium signaling regulates trafficking of familial hypocalciuric hypercalcemia (FHH) mutants of the calcium sensing receptor.

[familial hypocalciuric hypercalcemia]

Calcium-sensing receptors (CaSRs) regulate systemic Ca(2+) homeostasis. Loss-of-function mutations cause familial benign hypocalciuric hypercalcemia (FHH) or neonatal severe hyperparathyroidism (NSHPT). FHH/NSHPT mutations can reduce trafficking of CaSRs to the plasma membrane. CaSR signaling is potentiated by agonist-driven anterograde CaSR trafficking, leading to a new steady state level of plasma membrane CaSR, which is maintained, with minimal functional desensitization, as long as extracellular Ca(2+) is elevated. This requirement for CaSR signaling to drive CaSR trafficking to the plasma membrane led us to reconsider the mechanism(s) contributing to dysregulated trafficking of FHH/NSHPT mutants. We simultaneously monitored dynamic changes in plasma membrane levels of CaSR and intracellular Ca(2+), using a chimeric CaSR construct, which allowed explicit tracking of plasma membrane levels of mutant or wild-type CaSRs in the presence of nonchimeric partners. Expression of mutants alone revealed severe defects in plasma membrane targeting and Ca(2+) signaling, which were substantially rescued by coexpression with wild-type CaSR. Biasing toward heterodimerization of wild-type and FHH/NSHPT mutants revealed that intracellular Ca(2+) oscillations were insufficient to rescue plasma membrane targeting. Coexpression of the nonfunctional mutant E297K with the truncation CaSRΔ868 robustly rescued trafficking and Ca(2+) signaling, whereas coexpression of distinct FHH/NSHPT mutants rescued neither trafficking nor signaling. Our study suggests that rescue of FHH/NSHPT mutants requires a steady state intracellular Ca(2+) response when extracellular Ca(2+) is elevated and argues that Ca(2+) signaling by wild-type CaSRs rescues FHH mutant trafficking to the plasma membrane.

Diseases presenting "loss-of-function mutations" symptom

  • achondroplasia
  • alpha-thalassemia
  • aromatase deficiency
  • child syndrome
  • cowden syndrome
  • dystrophic epidermolysis bullosa
  • epidermolysis bullosa simplex
  • erythropoietic protoporphyria
  • esophageal adenocarcinoma
  • familial hypocalciuric hypercalcemia
  • harlequin ichthyosis
  • hirschsprung disease
  • kallmann syndrome
  • kindler syndrome
  • lamellar ichthyosis
  • neonatal adrenoleukodystrophy
  • pendred syndrome
  • werner syndrome
  • x-linked adrenoleukodystrophy

This symptom has already been validated