N-ethyl-N-nitrosourea-Induced Adaptor Protein 2 Sigma Subunit 1 (Ap2s1 ) Mutations Establish Ap2s1 Loss-of-Function Mice

JBMR Plus
Caroline M GorvinRajesh V Thakker

Abstract

The adaptor protein-2 sigma subunit (AP2σ), encoded by AP2S1, forms a heterotetrameric complex, with AP2α, AP2β, and AP2μ subunits, that is pivotal for clathrin-mediated endocytosis, and AP2σ loss-of-function mutations impair internalization of the calcium-sensing receptor (CaSR), a G-protein-coupled receptor, and cause familial hypocalciuric hypercalcemia type-3 (FHH3). Mice with AP2σ mutations that would facilitate investigations of the in vivo role of AP2σ, are not available, and we therefore embarked on establishing such mice. We screened >10,000 mice treated with the mutagen N-ethyl-N-nitrosourea (ENU) for Ap2s1 mutations and identified 5 Ap2s1 variants, comprising 2 missense (Tyr20Asn and Ile123Asn) and 3 intronic base substitutions, one of which altered the invariant donor splice site dinucleotide gt to gc. Three-dimensional modeling and cellular expression of the missense Ap2s1 variants did not reveal them to alter AP2σ structure or CaSR-mediated signaling, but investigation of the donor splice site variant revealed it to result in an in-frame deletion of 17 evolutionarily conserved amino acids (del17) that formed part of the AP2σ α1-helix, α1-β3 loop, and β3 strand. Heterozygous mutant mice (Ap2s1+/del17 ) were therefo...Continue Reading

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Citations

Nov 6, 2018·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Caroline M GorvinRajesh V Thakker
Oct 20, 2017·JCI Insight·Sarah A HowlesRajesh V Thakker
Dec 11, 2019·The Journal of Clinical Endocrinology and Metabolism·Caroline M GorvinRajesh V Thakker
Mar 10, 2020·The Journal of Clinical Endocrinology and Metabolism·Poonam DharmarajFadil M Hannan
Dec 12, 2018·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Stephen J Marx, David Goltzman
May 16, 2021·Pediatric Nephrology : Journal of the International Pediatric Nephrology Association·Caroline M Gorvin

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Methods Mentioned

BETA
PCR
biopsies
flow cytometry
electrophoresis
transfection
Cytomation
ELISA
genotyping
fluorescence microscopy
transfections

Software Mentioned

ImageJ
PyMOL Molecular Graphics System
MutationTasting
ClustalOmega
GraphPad Prism
Alternative Splicing Site Predictor
NIS Elements
Rotorgene Q Series
Polyphen
Excel

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