Mutational analysis of the adaptor protein 2 sigma subunit (AP2S1) gene: search for autosomal dominant hypocalcemia type 3 (ADH3).
BACKGROUND
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.


METHODS
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.


CONCLUSIONS
The absence of AP2S1 abnormalities in hypocalcemic patients, suggests that ADH3 may not occur or otherwise represents a rare hypocalcemic disorder.
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.
Angela
A
Rogers
M Andrew
MA
Nesbit
Fadil M
FM
Hannan
Sarah A
SA
Howles
Caroline M
CM
Gorvin
Treena
T
Cranston
Jeremy
J
Allgrove
John S
JS
Bevan
Gul
G
Bano
Caroline
C
Brain
Vipan
V
Datta
Ashley B
AB
Grossman
Shirley V
SV
Hodgson
Louise
L
Izatt
Lynne
L
Millar-Jones
Simon H
SH
Pearce
Lisa
L
Robertson
Peter L
PL
Selby
Brian
B
Shine
Katie
K
Snape
Justin
J
Warner
Rajesh V
RV
Thakker
D033962:Adaptor Protein Complex 2 / Q000235:genetics*; D034002:Adaptor Protein Complex sigma Subunits / Q000235:genetics*; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D006801:Humans; D053565:Hypercalciuria / Q000235:genetics*; D006996:Hypocalcemia / Q000235:genetics*; D007011:Hypoparathyroidism / Q000151:congenital* / Q000235:genetics; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
C510065:AP2S1 protein, human; D033962:Adaptor Protein Complex 2; D034002:Adaptor Protein Complex sigma Subunits