SFEBES2014 Poster Presentations Bone (30 abstracts)
Mutational analysis of the adaptor protein 2 sigma subunit (AP2S1) gene: search for autosomal dominant hypocalcaemia type 3 (ADH3)
Angela Rogers 1 , M Andrew Nesbit 1 , Fadil M Hannan 1 , Sarah A Howles 1 , Treena Cranston 2 , Jeremy Allgrove 3, , John S Bevan 5 , Gul Bano 6 , Caroline Brain 3 , Vipan Datta 7 , Shirley V Hodgson 8 , Louise Izatt 9 , Lynne Millar-Jones 10 , Simon H Pearce 11 , Lisa Robertson 12 , Peter L Selby 13 , Brian Shine 14 , Katie Snape 8 , Justin Warner 15 & Rajesh V Thakker 1
1Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, UK; 2Oxford Molecular Genetics Laboratory, Churchill Hospital, Oxford, UK; 3Department of Paediatric Endocrinology, Great Ormond Street Hospital, London, UK; 4Department of Paediatric Endocrinology, Royal London Hospital, London, UK; 5Department of Endocrinology, Aberdeen Royal Infirmary, Aberdeen, UK; 6Department of Diabetes and Endocrinology, St George’s Hospital, London, UK; 7Jenny Lind Children’s Department, Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK; 8Department of Clinical Genetics, St George’s Hospital, University of London, London, UK; 9Department of Clinical Genetics, Guy’s and St Thomas’ Foundation Trust, Guy’s Hospital, London, UK; 10Department of Paediatrics, Royal Glamorgan Hospital, Glamorgan, UK; 11Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, UK; 12Department of Clinical Genetics, Leicester Royal Infirmary, Leicester, UK; 13Department of Medicine, Manchester Royal Infirmary, Manchester, UK; 14Department of Clinical Biochemistry, John Radcliffe Hospital, Oxford, UK; 15Department of Paediatrics, University Hospital of Wales, Cardiff, UK.
Familial hypocalciuric hypercalcaemia types 1, 2, and 3 (FHH1, FHH2, and FHH3) are caused by loss-of-function mutations of the calcium-sensing receptor (CaSR), G-protein subunit α11 (Gα11) and adaptor protein 2 sigma subunit (AP2σ), respectively; whilst autosomal dominant hypocalcaemia types 1 and 2 (ADH1 and ADH2) are due to gain-of-function mutations of CaSR and Gα11, respectively. We therefore hypothesised that gain-of-function AP2σ mutations may result in ADH3, and investigated ADH patients who did not have CaSR or Gα11 mutations, for DNA sequence abnormalities of the AP2S1 gene, which encodes AP2σ. Sixteen patients (12 males and four females) with hypocalcaemia (albumin-adjusted calcium levels ranging from 0.94–2.03 mmol/l, normal range 2.10–2.60 mmol/l) in association with low or normal parathyroid hormone concentrations (ranging from <0.7–5.6 pmol/l, normal range 1.3–7.6 pmol/l; and from 2–26 ng/l, normal range 10–65 ng/l), consistent with ADH, but who did not have CaSR or Gα11 mutations, were included in the study. The 16 hypocalcaemic patients ranged in age at diagnosis or presentation from the neonatal period to 68 years old and 50% of patients presented with seizures or hypocalcaemic symptoms. More than 60% of the patients (n=16) had elevated serum phosphate concentrations. The urinary calcium:creatinine clearance ratio was high in 30% of thirteen patients. Leukocyte DNA was used for sequence analysis of the entire coding region and exon–intron boundaries of AP2S1.
However, AP2S1 coding region mutations were not detected in these 16 hypocalcaemic patients. Binomial probability analysis, using the assumption that AP2S1 mutations would occur in hypocalcaemic patients, at a prevalence of 20%, similar to that observed in FHH patients without CaSR or Gα11 mutations, indicated that the likelihood of detecting at least one AP2S1 mutation was >97% in this sample size of 16 hypocalcaemic patients. Thus, our findings suggest that ADH3 due to gain-of-function AP2σ mutations may be rare or non-existent.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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