A Homozygous [Cys25]PTH(1-84) Mutation That Impairs PTH/PTHrP Receptor Activation Defines a Novel Form of Hypoparathyroidism
Open Access
- 18 April 2015
- journal article
- research article
- Published by Oxford University Press (OUP) in Journal of Bone and Mineral Research
- Vol. 30 (10), 1803-1813
- https://doi.org/10.1002/jbmr.2532
Abstract
Hypocalcemia and hyperphosphatemia are encountered in idiopathic hypoparathyroidism (IHP) and pseudohypoparathyroidism type Ib (PHP1B). In contrast to PHP1B, which is caused by resistance toward parathyroid hormone (PTH), the genetic defects leading to IHP impair production of this important regulator of mineral ion homeostasis. So far, only five PTH mutations were shown to cause IHP, each of which is located in the hormone's pre‐pro leader segment and thus impair hormone secretion. In three siblings affected by IHP, we now identified a homozygous arginine‐to‐cysteine mutation at position 25 (R25C) of the mature PTH(1‐84) polypeptide; heterozygous family members are healthy. Depending on the assay used for evaluating these patients, plasma PTH levels were either low or profoundly elevated, thus leading to ambiguities regarding the underlying diagnosis, namely IHP or PHP1B. Consistent with increased PTH levels, recombinant [Cys25]PTH(1‐84) and wild‐type PTH(1‐84) were secreted equally well by transfected COS‐7 cells. However, synthetic [Cys25]PTH(1‐34) was found to have a lower binding affinity for the PTH receptor type‐1 (PTH1R) than PTH(1‐34) and consequently a lower efficiency for stimulating cAMP formation in cells expressing this receptor. Consistent with these in vitro findings, long‐term infusion of [Cys25]PTH(1‐34) resulted only in minimal calcemic and phosphaturic responses, despite readily detectable levels of [Cys25]PTH(1‐34) in plasma. The mineral ion abnormalities observed in the three IHP patients are thus most likely caused by the inherited homozygous missense PTH mutation, which reduces bioactivity of the secreted hormone. Based on these findings, screening for PTH(1‐84) mutations should be considered when clinical and laboratory findings are consistent with PHP1B, but GNAS methylation changes have been excluded. Differentiating between IHP and PHP1B has considerable implications for genetic counseling, therapy, and long‐term outcome because treatment of IHP patients with inappropriately high doses of active vitamin D and calcium can contribute to development of nephrocalcinosis and chronic kidney disease. © 2015 American Society for Bone and Mineral Research.Keywords
This publication has 68 references indexed in Scilit:
- Identification and characterization of C106R, a novel mutation in the DNA‐binding domain of GCMB, in a family with autosomal‐dominant hypoparathyroidismClinical Endocrinology, 2011
- Madelung-Like Deformity in Pseudohypoparathyroidism Type 1bJournal of Clinical Endocrinology & Metabolism, 2011
- Paternal uniparental isodisomy of the entire chromosome 20 as a molecular cause of pseudohypoparathyroidism type Ib (PHP-Ib)Bone, 2010
- Deletion of the NoncodingGNASAntisense Transcript Causes Pseudohypoparathyroidism Type Ib and Biparental Defects ofGNASMethylationin cisJournal of Clinical Endocrinology & Metabolism, 2010
- Presence and significance of a R110W mutation in the DNA-binding domain of GCM2 gene in patients with isolated hypoparathyroidism and their family membersActa Endocrinologica, 2010
- The role of GNAS and other imprinted genes in the development of obesityInternational Journal of Obesity, 2009
- Structural Basis for Parathyroid Hormone-related Protein Binding to the Parathyroid Hormone Receptor and Design of Conformation-selective PeptidesJournal of Biological Chemistry, 2009
- The ClinSeq Project: Piloting large-scale genome sequencing for research in genomic medicineGenome Research, 2009
- Dominant-NegativeGCMBMutations Cause an Autosomal Dominant Form of HypoparathyroidismJournal of Clinical Endocrinology & Metabolism, 2008
- Identification of a novel mutation disrupting the DNA binding activity of GCM2 in autosomal recessive familial isolated hypoparathyroidismJournal of Medical Genetics, 2005