PMID- 24708097 OWN - NLM STAT- MEDLINE DCOM- 20140929 LR - 20211021 IS - 1945-7197 (Electronic) IS - 0021-972X (Print) IS - 0021-972X (Linking) VI - 99 IP - 7 DP - 2014 Jul TI - Mutational analysis of the adaptor protein 2 sigma subunit (AP2S1) gene: search for autosomal dominant hypocalcemia type 3 (ADH3). PG - E1300-5 LID - 10.1210/jc.2013-3909 [doi] AB - CONTEXT: Autosomal dominant hypocalcemia (ADH) types 1 and 2 are due to calcium-sensing receptor (CASR) and G-protein subunit-alpha11 (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 (AP2sigma 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. FAU - Rogers, Angela AU - Rogers A AD - Academic Endocrine Unit (A.R., M.A.N., F.M.H., S.A.H., C.M.G., R.V.T.), Nuffield Department of Clinical Medicine, and Academic Endocrine Unit (A.R., M.A.N., F.M.H., S.A.H., C.M.G., R.V.T.), Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7LJ, United Kingdom; Oxford Molecular Genetics Laboratory (T.C.) and Oxford Centre for Diabetes, Endocrinology, and Metabolism (A.B.G.), Churchill Hospital, Oxford OX3 7LJ, United Kingdom; Department of Paediatric Endocrinology (J.A., C.B.), Great Ormond Street Hospital, London WC1N 3JH, United Kingdom; Department of Paediatric Endocrinology (J.A.), Royal London Hospital, London E1 1BB, United Kingdom; Department of Endocrinology (J.S.B.), Aberdeen Royal Infirmary, Aberdeen AB25 2ZN, United Kingdom; Departments of Diabetes and Endocrinology (G.B.) and Clinical Genetics (S.V.H., K.S.), St George's Hospital, London SW17 0RE, United Kingdom; Jenny Lind Children's Department (V.D.), Norfolk and Norwich University Hospitals National Health Service Foundation Trust, Norfolk NR4 7UY, United Kingdom; Department of Clinical Genetics (L.I.), Guy's and St Thomas' Foundation Trust, Guy's Hospital, London SE1 9RT, United Kingdom; Department of Paediatrics (L.M.-J.), Royal Glamorgan Hospital, Glamorgan CF72 8XR, United Kingdom; Endocrine Unit (S.H.P.), Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, United Kingdom; Department of Clinical Genetics (L.R.), Leicester Royal Infirmary, Leicester LE1 5WW, United Kingdom; Department of Medicine (P.L.S.), Manchester Royal Infirmary, Manchester M13 9WL, United Kingdom; Department of Clinical Biochemistry (B.S.), John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom; and Department of Paediatrics (J.W.), University Hospital of Wales, Cardiff CF14 4XW, United Kingdom. FAU - Nesbit, M Andrew AU - Nesbit MA FAU - Hannan, Fadil M AU - Hannan FM FAU - Howles, Sarah A AU - Howles SA FAU - Gorvin, Caroline M AU - Gorvin CM FAU - Cranston, Treena AU - Cranston T FAU - Allgrove, Jeremy AU - Allgrove J FAU - Bevan, John S AU - Bevan JS FAU - Bano, Gul AU - Bano G FAU - Brain, Caroline AU - Brain C FAU - Datta, Vipan AU - Datta V FAU - Grossman, Ashley B AU - Grossman AB FAU - Hodgson, Shirley V AU - Hodgson SV FAU - Izatt, Louise AU - Izatt L FAU - Millar-Jones, Lynne AU - Millar-Jones L FAU - Pearce, Simon H AU - Pearce SH FAU - Robertson, Lisa AU - Robertson L FAU - Selby, Peter L AU - Selby PL FAU - Shine, Brian AU - Shine B FAU - Snape, Katie AU - Snape K FAU - Warner, Justin AU - Warner J FAU - Thakker, Rajesh V AU - Thakker RV LA - eng GR - Wellcome Trust/United Kingdom GR - G1000467/MRC_/Medical Research Council/United Kingdom GR - G9825289/MRC_/Medical Research Council/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140407 PL - United States TA - J Clin Endocrinol Metab JT - The Journal of clinical endocrinology and metabolism JID - 0375362 RN - 0 (AP2S1 protein, human) RN - 0 (Adaptor Protein Complex 2) RN - 0 (Adaptor Protein Complex sigma Subunits) RN - Hypercalciuric Hypocalcemia, Familial SB - IM MH - Adaptor Protein Complex 2/*genetics MH - Adaptor Protein Complex sigma Subunits/*genetics MH - Adult MH - Child MH - Child, Preschool MH - DNA Mutational Analysis MH - Female MH - Gene Frequency MH - Humans MH - Hypercalciuria/*genetics MH - Hypocalcemia/*genetics MH - Hypoparathyroidism/*congenital/genetics MH - Infant MH - Infant, Newborn MH - Male MH - Middle Aged MH - Polymorphism, Single Nucleotide PMC - PMC4447854 EDAT- 2014/04/09 06:00 MHDA- 2014/09/30 06:00 PMCR- 2015/07/01 CRDT- 2014/04/09 06:00 PHST- 2014/04/09 06:00 [entrez] PHST- 2014/04/09 06:00 [pubmed] PHST- 2014/09/30 06:00 [medline] PHST- 2015/07/01 00:00 [pmc-release] AID - 13-3909 [pii] AID - 10.1210/jc.2013-3909 [doi] PST - ppublish SO - J Clin Endocrinol Metab. 2014 Jul;99(7):E1300-5. doi: 10.1210/jc.2013-3909. Epub 2014 Apr 7.