ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2019) 65 OC3.5 | DOI: 10.1530/endoabs.65.OC3.5

Mutational analysis of a patient with familial hypocalciuric hypercalcaemia identifies a novel p.Ser182Cys mutation, which is predicted to disrupt the calcium sensing receptor (CaSR) extracellular domain

Ultan Healy1, Mie Kronborg Olesen2, Bahram Jafar-Mohammadi1, Fadil M Hannan2 & Rajesh V Thakker2

1Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; 2Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, UK

Familial hypocalciuric hypercalcaemia (FHH) is an inherited disorder of calcium homeostasis, which is caused by germline loss-of-function mutations of the calcium-sensing receptor (CaSR) in ˜70% of cases. We report a 22 year old woman who was referred with asymptomatic hypercalcaemia. Biochemical investigations revealed hypercalcaemia on 3 of 4 occasions with adjusted serum calcium ranging from 2.59–2.80 mmol/l (normal range 2.20–2.60 mmol/l). Parathyroid hormone levels ranged from 4.2–6.5 pmol/l (normal range 1.6–7.2 pmol/l). Urinary calcium excretion was 3.5 mmol in 24 hours (normal range 2.5–7.5 mmol/24 h). Spot urinary calcium creatinine clearance ratio was calculated at 0.0095 (normal >0.01). Investigations were consistent with a diagnosis of FHH, prompting genetic testing. Molecular analysis of the CaSR gene revealed a novel heterozygous single base pair substitution, Cytosine to Guanine, at nucleotide c.545. This resulted in the substitution of an evolutionarily conserved serine residue for a mutant cysteine residue at position 182 of the CaSR protein. Modelling studies using the crystal structure of the dimeric human CaSR revealed that the wild-type Ser182 residue is located within a densely packed region of the extracellular domain, which is critical for ligand binding and receptor dimerization. The wild-type Ser182 residue was shown to interact with multiple CaSR residues including Gln164, Ile162, and Ala154, whereas the mutant Cys182 residue is predicted to disrupt the interaction with the nearby Ile162 residue and additionally influence other CaSR extracellular domain residues (Tyr161 and Leu461) through effects on Van der Waals interactions. Thus, these studies involving an FHH patient have identified a novel missense mutation, which is predicted to impair the function of the CaSR extracellular domain.

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