CASR – Autosomal Dominant Hypocalcemia Type 1

Autosomal dominant hypocalcemia type 1 (ADH1) is a rare endocrine disorder characterized by hypocalcemia and inappropriately low parathyroid hormone (PTH) levels due to activating variants in the calcium-sensing receptor, CASR (HGNC:1514). Initial reports in 1996 identified heterozygous missense mutations in two families with hypoparathyroidism and hypercalciuria, establishing causation by gain-of-function CASR variants (PMID:8733126). CASR encodes a G-protein–coupled receptor expressed in parathyroid glands and the renal tubule, where it modulates PTH secretion and calcium reabsorption.

ADH1 presents with persistent hypocalcemia (99% of patients) and variable hypercalciuria, leading to renal complications such as nephrocalcinosis and nephrolithiasis (PMID:35879818). Seizures occur in approximately 39% of cases, and intracerebral calcifications have been reported in patients with prolonged disease (PMID:35879818). Some individuals exhibit a Bartter-like phenotype with secondary hypokalemia and metabolic alkalosis, reflecting distal tubular sodium-chloride cotransporter (NCCT) dysfunction (PMID:26323216).

Genetic evidence is robust: over 190 unrelated ADH1 patients have been described, with segregation in multiple pedigrees including a three-generation kindred of seven affected individuals (PMID:36812896) and documented parental mosaicism (PMID:12915654). More than 113 unique activating CASR variants have been identified, spanning missense substitutions, splice-site mutations, and small indels. A recurrent variant, c.2363T>G (p.Phe788Cys), has been observed in multiple patients with intracerebral calcifications and myoclonus (PMID:35402765).

Functional studies demonstrate that ADH1 variants shift the receptor's calcium sensitivity leftward. The p.Leu125Pro mutation reduces the EC50 for extracellular Ca²⁺, leading to exaggerated receptor activation and a Bartter-like syndrome with hypokalemia (PMID:12191970). Structural analyses predict that p.Phe788Cys disrupts stabilizing aromatic interactions in transmembrane domain 5, favoring the active receptor conformation (PMID:35402765).

Calcimimetic agents can modulate mutant receptor activity: NPS R-568 and Evocalcet enhance signaling of certain extracellular and cytoplasmic domain mutants in vitro, suggesting potential targeted therapies for symptomatic ADH1 (PMID:18796518).

In summary, definitive evidence links gain-of-function CASR variants to ADH1 via autosomal dominant inheritance, with extensive case reports, segregation in multiple families, and concordant functional data. Genetic diagnosis informs clinical management, including judicious use of calcium/vitamin D and potential calcimimetic therapy to balance serum calcium against hypercalciuria.

References

• Human Molecular Genetics • 1996 • Mutations in the Ca(2+)-sensing receptor gene cause autosomal dominant and sporadic hypoparathyroidism. PMID:8733126
• Clinical and Experimental Nephrology • 2016 • Pathogenesis of hypokalemia in autosomal dominant hypocalcemia type 1. PMID:26323216
• Journal of Bone and Mineral Research • 2022 • Autosomal Dominant Hypocalcemia Type 1: A Systematic Review. PMID:35879818
• Journal of the Endocrine Society • 2022 • Autosomal Dominant Hypocalcemia Type 1 (ADH1) Associated With Myoclonus and Intracerebral Calcifications. PMID:35402765
• Journal of the American Society of Nephrology • 2002 • Functional characterization of a calcium-sensing receptor mutation in severe autosomal dominant hypocalcemia with a Bartter-like syndrome. PMID:12191970
• The Journal of Clinical Endocrinology and Metabolism • 2008 • Novel inactivating mutations of the calcium-sensing receptor: the calcimimetic NPS R-568 improves signal transduction of mutant receptors. PMID:18796518

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