Back to Search Start Over

Mutational Analysis of the Adaptor Protein 2 Sigma Subunit (AP2S1) Gene: Search for Autosomal Dominant Hypocalcemia Type 3 (ADH3)

Authors :
Lynne Millar-Jones
Louise Izatt
Sarah A. Howles
M. Andrew Nesbit
Lisa Robertson
Peter Selby
Caroline M Gorvin
John S. Bevan
Angela Rogers
Shirley Hodgson
Treena Cranston
Simon H. S. Pearce
Caroline Brain
Gul Bano
Jeremy Allgrove
Brian Shine
Fadil M. Hannan
Katie Snape
Ashley B. Grossman
Vipan Datta
Rajesh V. Thakker
Justin T. Warner
Source :
The Journal of Clinical Endocrinology & Metabolism. 99:E1300-E1305
Publication Year :
2014
Publisher :
The Endocrine Society, 2014.

Abstract

CONTEXT: Autosomal dominant hypocalcemia (ADH) types 1 and 2 are due to calcium-sensing receptor (CASR) and G-protein subunit-α11 (GNA11) gain-of-function mutations, respectively, whereas CASR and GNA11 loss-of-function mutations result in familial hypocalciuric hypercalcemia (FHH) types 1 and 2, respectively. Loss-of-function mutations of adaptor protein-2 sigma subunit (AP2σ 2), encoded by AP2S1, cause FHH3, and we therefore sought for gain-of-function AP2S1 mutations that may cause an additional form of ADH, which we designated ADH3. OBJECTIVE: The objective of the study was to investigate the hypothesis that gain-of-function AP2S1 mutations may cause ADH3. DESIGN: The sample size required for the detection of at least one mutation with a greater than 95% likelihood was determined by binomial probability analysis. Nineteen patients (including six familial cases) with hypocalcemia in association with low or normal serum PTH concentrations, consistent with ADH, but who did not have CASR or GNA11 mutations, were ascertained. Leukocyte DNA was used for sequence and copy number variation analysis of AP2S1. RESULTS: Binomial probability analysis, using the assumption that AP2S1 mutations would occur in hypocalcemic patients at a prevalence of 20%, which is observed in FHH patients without CASR or GNA11 mutations, indicated that the likelihood of detecting at least one AP2S1 mutation was greater than 95% and greater than 98% in sample sizes of 14 and 19 hypocalcemic patients, respectively. AP2S1 mutations and copy number variations were not detected in the 19 hypocalcemic patients. CONCLUSION: The absence of AP2S1 abnormalities in hypocalcemic patients, suggests that ADH3 may not occur or otherwise represents a rare hypocalcemic disorder.

Details

ISSN :
19457197 and 0021972X
Volume :
99
Database :
OpenAIRE
Journal :
The Journal of Clinical Endocrinology & Metabolism
Accession number :
edsair.doi.dedup.....417d9256b4f6e107f1a44377cb86d55b
Full Text :
https://doi.org/10.1210/jc.2013-3909