SFEBES2014 Poster Presentations Bone (30 abstracts)
Identification of 12 adaptor protein-2 sigma 2 subunit mutations in familial hypocalciuric hypercalcaemia type 3 and expansion of phenotypic spectrum.
Angela Rogers 1 , Fadil M Hannan 1 , Sarah A Howles 1 , Treena Cranston 2 , Clare E Thakker 1 , Detlef Bockenhauer 3 , Rosalind Brown 4 , Jacqueline A Cook 5 , Ken Darzy 6 , Sarah Ehtisham 7 , Tony Hulse 8 , Dhavendra Kumar 9 , Malachi McKenna 10 , John McKnight 11 , Zulf Mughal 7 , Simon H Pearce 12 , Tristan Richardson 13 , Isabelle Scheers 14 , Timothy Wang 15 , M Andrew Nesbit 1 & Rajesh V Thakker 1
1Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, UK; 2Oxford Molecular Genetics Laboratory, Churchill Hospital, Oxford, UK; 3UCL Institute of Child Health and Great Ormond Street Hospital for Children, London, UK; 4Division of Endocrinology, Boston Children’s Hospital, Boston, Massachusetts, USA; 5Clinical Genetics Department, Sheffield Children’s Hospital NHS Foundation Trust, Sheffield, UK; 6Queen Elizabeth II Hospital, Welwyn Garden City, UK; 7Department of Paediatric Endocrinology, Royal Manchester Children’s Hospital, Manchester, UK; 8Department of Paediatrics, St Thomas’ Hospital, London, UK; 9Department of Clinical Genetics, University Hospital Wales, Cardiff, UK; 10Department of Endocrinology, St Vincent’s University Hospital, Dublin, Ireland; 11Department of Endocrinology and Diabetes, Western General Hospital, Edinburgh, UK; 12Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, UK; 13Department of Endocrinology, Royal Bournemouth Hospital, Bournemouth, UK; 14Department of Paediatrics, Cliniques Universitaires Saint-Luc, Brussels, Belgium; 15Clinical Biochemistry Department, Frimley Park Hospital, Surrey, UK.
Familial hypocalciuric hypercalcaemia (FHH) is an autosomal dominant disorder characterized by hypercalcaemia and inappropriately low urinary calcium excretion, and is occasionally associated with acute pancreatitis. FHH can be classified into three types: FHH type 1, caused by loss-of-function mutations of the calcium-sensing receptor (CaSR), which accounts for >65% of cases; FHH type 2, due to loss-of-function mutations of the G-protein α 11 subunit (Gα11), of which two cases have been identified; and FHH type 3 resulting from loss-of-function mutations in the ubiquitously expressed adaptor protein-2 sigma subunit (AP2σ), encoded by AP2S1, of which 14 patients and families have been reported. The aim of this study was to investigate a further 45 FHH probands (15 males and 30 females), who did not harbour CaSR or Gα11 mutations, for the presence of AP2σ mutations. Leukocyte DNA was used for mutational analysis of the entire coding region and exon–intron boundaries. DNA sequence analysis identified AP2σ mutations in 12 probands (Four males and eight females, age at diagnosis ranging from 9 years to 48 years old), which all affected the Arg15 residue, and comprised three Arg15Cys, five Arg15Leu, and four Arg15His AP2σ mutations. Two unrelated, female patients aged 14 and 15 years old harboured de novo Arg15Leu AP2σ mutations; the 15-year-old girl also had short stature, learning difficulties and an atrial-septal defect, and the 14-year-old girl also had short stature, learning difficulties and recurrent episodes of acute pancreatitis. In summary, 12 AP2σ mutations were identified in 45 FHH probands, indicating that AP2σ mutations account for >25% of FHH patients without CaSR and Gα11 mutations. Thus, our findings indicate that AP2S1 mutational analysis should be undertaken in FHH patients who do not have CaSR mutations, and that patients harbouring an Arg15Leu AP2σ mutation may present with additional non-calciotropic phenotypes.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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