A Hong Kong Chinese kindred with familial hypocalciuric hypercalcaemia caused by AP2S1 mutation

Abstract

Familial hypocalciuric hypercalcaemia (FHH) is a genetic disorder of altered calcium homeostasis. Mutations in the CASR, GNA11 and AP2S1 genes have been reported to cause FHH. We report a Hong Kong Chinese kindred with FHH type 3 (FHH3) caused by mutations in AP2S1. The proband, a 51-year-old woman with hypercalcaemia, was initially diagnosed to have primary hyperparathyroidism but repeated parathyroidectomy failed to normalize her plasma calcium concentrations. Later, FHH was suspected and yet no mutations were identified in the CASR gene which causes FHH type 1 (FHH1), the most common form of FHH. Genetic testing of AP2S1 revealed a heterozygous c.43C>T (p.Arg15Cys) mutation, confirming the diagnosis of FHH3. The elder brother and niece of the proband, who both have hypercalcaemia, were found to harbour the same mutation. To our knowledge, this is the first Chinese kindred of FHH3 reported in the English literature.

Role of adaptin protein complexes in intracellular trafficking and their impact on diseases

“…Controlling the expression of AP2M1 was proposed as a potentially effective treatment for cystic fibrosis, a genetic disorder caused by defective cellular trafficking [126], demonstrating its potential as a target gene for diverse diseases. Finally, the small subunit AP2S1 was shown to be critical for cellular calcium-sensing receptor activity [127], and AP2S1 mutations were reported to result in familial hypocalciuric hypercalcemia type 3, which causes high calcium levels in the bloodstream [128] Notably, most studies involving AP2S1 were linked to this genetic disease [129][130][131][132][133][134][135]. To date, with the exception of this report, AP2S1 has only been detected during the screening of other AP2 subunits that affect obesity [88], which suggests that its major function is in the calcium-sensing pathway.…”