Ap2s1 mutation causes hypercalcaemia in mice and impairs interaction between calcium-sensing receptor and adaptor protein-2.
Adaptor Protein Complex 2
/ genetics
Adaptor Protein Complex sigma Subunits
/ genetics
Animals
Bone Density
/ genetics
CRISPR-Cas Systems
/ genetics
Calcium
/ metabolism
Cinacalcet
/ pharmacology
Disease Models, Animal
Fibroblast Growth Factor-23
/ genetics
Gene Editing
Humans
Hypercalcemia
/ drug therapy
Mice
Mutation
/ genetics
Phenotype
Receptors, Calcium-Sensing
/ genetics
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
29 05 2021
29 05 2021
Historique:
received:
26
11
2020
revised:
09
02
2021
accepted:
26
02
2021
pubmed:
18
3
2021
medline:
4
3
2022
entrez:
17
3
2021
Statut:
ppublish
Résumé
Adaptor protein 2 (AP2), a heterotetrameric complex comprising AP2α, AP2β2, AP2μ2 and AP2σ2 subunits, is ubiquitously expressed and involved in endocytosis and trafficking of membrane proteins, such as the calcium-sensing receptor (CaSR), a G-protein coupled receptor that signals via Gα11. Mutations of CaSR, Gα11 and AP2σ2, encoded by AP2S1, cause familial hypocalciuric hypercalcaemia types 1-3 (FHH1-3), respectively. FHH3 patients have heterozygous AP2S1 missense Arg15 mutations (p.Arg15Cys, p.Arg15His or p.Arg15Leu) with hypercalcaemia, which may be marked and symptomatic, and occasional hypophosphataemia and osteomalacia. To further characterize the phenotypic spectrum and calcitropic pathophysiology of FHH3, we used CRISPR/Cas9 genome editing to generate mice harboring the AP2S1 p.Arg15Leu mutation, which causes the most severe FHH3 phenotype. Heterozygous (Ap2s1+/L15) mice were viable, and had marked hypercalcaemia, hypermagnesaemia, hypophosphataemia, and increases in alkaline phosphatase activity and fibroblast growth factor-23. Plasma 1,25-dihydroxyvitamin D was normal, and no alterations in bone mineral density or bone turnover were noted. Homozygous (Ap2s1L15/L15) mice invariably died perinatally. Co-immunoprecipitation studies showed that the AP2S1 p.Arg15Leu mutation impaired protein-protein interactions between AP2σ2 and the other AP2 subunits, and also with the CaSR. Cinacalcet, a CaSR positive allosteric modulator, decreased plasma calcium and parathyroid hormone concentrations in Ap2s1+/L15 mice, but had no effect on the diminished AP2σ2-CaSR interaction in vitro. Thus, our studies have established a mouse model that is representative for FHH3 in humans, and demonstrated that the AP2S1 p.Arg15Leu mutation causes a predominantly calcitropic phenotype, which can be ameliorated by treatment with cinacalcet.
Identifiants
pubmed: 33729479
pii: 6174626
doi: 10.1093/hmg/ddab076
pmc: PMC8165646
doi:
Substances chimiques
Adaptor Protein Complex 2
0
Adaptor Protein Complex sigma Subunits
0
Ap2s1 protein, mouse
0
Receptors, Calcium-Sensing
0
Fibroblast Growth Factor-23
7Q7P4S7RRE
Calcium
SY7Q814VUP
Cinacalcet
UAZ6V7728S
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
880-892Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UP_1502/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 106995/Z/15/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 205011/Z/16/Z
Pays : United Kingdom
Informations de copyright
© The Author(s) 2021. Published by Oxford University Press.
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