Molecular and clinical analysis of a neonatal severe hyperparathyroidism case caused by a stop mutation in the calcium-sensing receptor extracellular domain representing in effect a human 'knockout'

Ward, D. T., Mughal, M. Z., Ranieri, M., Dvorak-Ewell, M. M., Valenti, G. and Riccardi, Daniela ORCID: https://orcid.org/0000-0002-7322-3163 2013. Molecular and clinical analysis of a neonatal severe hyperparathyroidism case caused by a stop mutation in the calcium-sensing receptor extracellular domain representing in effect a human 'knockout'. European Journal of Endocrinology 169 (1) , K1-K7. 10.1530/EJE-13-0094

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Abstract

Objective: Loss-of-function calcium-sensing receptor (CAR) mutations cause elevated parathyroid hormone (PTH) secretion and hypercalcaemia. Although full Car deletion is possible in mice, most human CAR mutations result from a single amino acid substitution that maintains partial function. However, here, we report a case of neonatal severe hyperparathyroidism (NSHPT) in which the truncated CaR lacks any transmembrane domain (CaRR392X), in effect a full CAR ‘knockout’. Case report: The infant (daughter of distant cousins) presented with hypercalcaemia (5.5–6 mmol/l corrected calcium (2.15–2.65)) and elevated PTH concentrations (650–950 pmol/l (12–81)) together with skeletal demineralisation. NSHPT was confirmed by CAR gene sequencing (homozygous c.1174C-to-T mutation) requiring total parathyroidectomy during which only two glands were located and removed, resulting in normalisation of her serum PTH/calcium levels. Design and methods: The R392X stop codon was inserted into human CAR and the resulting mutant (CaRR392X) expressed transiently in HEK-293 cells. Results: CaRR392X expressed as a 54 kDa dimeric glycoprotein that was undetectable in conditioned medium or in the patient's urine. The membrane localisation observed for wild-type CaR in parathyroid gland and transfected HEK-293 cells was absent from the proband's parathyroid gland and from CaRR392X-transfected cells. Expression of the mutant was localised to endoplasmic reticulum consistent with its lack of functional activity. Conclusions: Intriguingly, the patient remained normocalcaemic throughout childhood (2.5 mM corrected calcium, 11 pg/ml PTH (10–71), age 8 years) but exhibited mild asymptomatic hypocalcaemia at age 10 years, now treated with 1-hydroxycholecalciferol and Ca2+ supplementation. Despite representing a virtual CAR knockout, the patient displays no obvious pathologies beyond her calcium homeostatic dysfunction.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Subjects:	Q Science > QH Natural history > QH301 Biology Q Science > QP Physiology
Publisher:	BioScientifica
ISSN:	0804-4643
Last Modified:	24 Oct 2022 11:58
URI:	https://orca.cardiff.ac.uk/id/eprint/49904

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