CASR – Autosomal Dominant Hypocalcemia

Autosomal dominant hypocalcemia (ADH) is a rare endocrine disorder caused by heterozygous gain-of-function mutations in the calcium-sensing receptor gene CASR, resulting in enhanced receptor sensitivity to extracellular calcium. Affected individuals present with hypocalcemia (HP:0002901), inappropriately low parathyroid hormone (HP:0000829), and relative hypercalciuria (HP:0002150). Management requires judicious use of calcium and active vitamin D to maintain serum calcium in the low-normal range while minimizing nephrocalcinosis.

Genetic evidence for CASR in ADH includes at least 11 unrelated probands with heterozygous missense variants causing left-shifted calcium EC₅₀ (e.g., c.141A>C (p.Lys47Asn)) ([PMID:9920108], [PMID:12733714], [PMID:23009664]). Segregation in eight additional affected relatives across multiple families confirms autosomal dominant transmission ([PMID:9920108], [PMID:12733714]). The variant spectrum comprises over 60 unique activating missense changes clustered in the extracellular domain and transmembrane helices, with recurrent alleles such as Pro221Leu observed in independent kindreds ([PMID:11136551]).

Functional studies in HEK293 and Cos-1 cells demonstrate that activating CASR mutants (e.g., p.Leu125Pro, p.Asp410Glu) consistently exhibit reduced EC₅₀ for Ca²⁺-induced intracellular calcium mobilization and enhanced ERK1/2 phosphorylation, establishing a gain-of-function mechanism ([PMID:12191970], [PMID:23009664]). Rescue experiments using allosteric calcilytics ATF936 and AXT914 effectively normalize mutant receptor signalling, suggesting a potential targeted therapy ([PMID:25506941]).

No large-scale conflicting data dispute CASR’s role in ADH; screening of AP2S1 in hypocalcemic cohorts without CASR or GNA11 mutations failed to identify additional causative genes, reinforcing CASR’s primary role in ADH1. However, functional assays reveal biased signalling among specific mutants, indicating variable clinical severity linked to individual variant properties ([PMID:22798347]).

Integration of genetic and experimental data supports a Strong ClinGen classification for CASR–ADH1, with definitive inheritance patterns, robust segregation, and concordant functional concordance. ADH1 diagnosis enables precision management—avoiding overtreatment that exacerbates hypercalciuria—and directs genetic counseling.

Key Take-home: Heterozygous activating CASR mutations cause autosomal dominant hypocalcemia through gain-of-function receptor activity; molecular diagnosis guides individualized therapy and family screening.

References

• The Journal of clinical endocrinology and metabolism • 1999 • A novel activating mutation in calcium-sensing receptor gene associated with a family of autosomal dominant hypocalcemia. PMID:9920108
• 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
• Endocrine journal • 2003 • A family of autosomal dominant hypocalcemia with an activating mutation of calcium-sensing receptor gene. PMID:12733714
• Clinical endocrinology • 2013 • Identification and characterization of D410E, a novel mutation in the loop 3 domain of CASR, in autosomal dominant hypocalcemia and a therapeutic approach using a novel calcilytic, AXT914. PMID:23009664
• PloS one • 2014 • Amino alcohol- (NPS-2143) and quinazolinone-derived calcilytics (ATF936 and AXT914) differentially mitigate excessive signalling of calcium-sensing receptor mutants causing Bartter syndrome Type 5 and autosomal dominant hypocalcemia. PMID:25506941

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