Hypercalcaemia

Gene: AP2S1

Green List (high evidence)

11 individuals with 9 non-synonymous AP2σ variants (Arg3His, Arg15His (x3), Ala44Thr, Phe52Tyr, Arg61His, Thr112Met, Met117Ile, Glu122Gly and Glu142Lys).

Structural modelling of the 8 novel variants (Arg3His, Ala44Thr, Phe52Tyr, Arg61His, Thr112Met, Met117Ile, Glu122Gly and Glu142Lys) predicted that the Arg3His, Thr112Met, Glu122Gly and Glu142Lys variants would disrupt polar contacts within the AP2σ subunit or affect the interface between the AP2σ and AP2α subunits. Functional analyses of all eight AP2σ variants in CaSR-expressing cells demonstrated that the Thr112Met, Met117Ile and Glu142Lys variants, located in the AP2σ α4-α5 helical region that forms an interface with AP2α, impaired CaSR-mediated intracellular calcium (Cai2+) signalling, consistent with a loss of function, and this was rectified by treatment with the CaSR positive allosteric modulator cinacalcet.

Created: 6 Sep 2024, 6:24 a.m. | Last Modified: 6 Sep 2024, 6:24 a.m.

Panel Version: 1.2

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Hypocalciuric hypercalcaemia, type III, MIM# 600740; MONDO:0010926

Publications

• PMID: 29325022

Green List (high evidence)

More than 5 unrelated families reported, mouse models. Missense variants at codon 15 are recurrent.

Created: 5 Apr 2021, 8:52 a.m. | Last Modified: 5 Apr 2021, 8:52 a.m.

Panel Version: 0.15

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Hypocalciuric hypercalcaemia, type III, MIM# 600740; MONDO:0010926

Publications

• 23222959
• 33729479
• 33168530
• 3204769
• 31723423
• 29479578