Homozygous Ser-1 to Pro-1 mutation in parathyroid hormone identified in hypocalcemic patients results in secretion of a biologically inactive pro-hormone

Author:

Hanna Patrick1,Khatri Ashok1,Choi Shawn1,Brabant Severine2ORCID,Gild Matti L.345,Piketty Marie L.2,Francou Bruno6ORCID,Prié Dominique2,Potts John T.1ORCID,Clifton-Bligh Roderick J.345,Linglart Agnès78ORCID,Gardella Thomas J.1,Jüppner Harald19

Affiliation:

1. Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114

2. Université Paris Cité, Institut Necker Enfants Malades, Institut National de la Santé et de la Recherche Médicale U1151, Service des Explorations Fonctionnelles, Hôpital Necker Enfants Malades, Assistance Publique – Hôpitaux de Paris, Paris 75015, France

3. Department of Endocrinology Royal North Shore Hospital, St Leonards, NSW 2065, Australia

4. Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW 2050, Australia

5. Cancer Genetics Laboratory, Kolling Institute of Medical Research, St. Leonards, NSW 2064, Australia

6. Université Paris-Saclay, Institut National de la Santé et de la Recherche Médicale, Physiologie et Physiopathologie Endocrinienne, Assistance Publique – Hôpitaux de Paris, Department of Molecular Genetics, Bicêtre Paris-Saclay Hospital, Le Kremlin Bicêtre 94270, France

7. Assistance Publique – Hôpitaux de Paris, Endocrinology and Diabetology for Children, Bicêtre Paris Saclay Hospital, Le Kremlin Bicêtre 94270, France

8. Université Paris Saclay, Institut National de la Santé et de la Recherche Médicale, Physiologie et Physiopathologie Endocrinienne, Bicêtre Paris Saclay Hospital, Le Kremlin Bicêtre 94270, France

9. Pediatric Nephrology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114

Abstract

Like other secreted peptides, nascent parathyroid hormone (PTH) is synthesized with a pre- and a pro-sequence (25 and 6 amino acids, respectively). These precursor segments are sequentially removed in parathyroid cells before packaging into secretory granules. Three patients from two unrelated families who presented during infancy with symptomatic hypocalcemia were found to have a homozygous serine (S) to proline (P) change affecting the first amino acid of the mature PTH. Unexpectedly, biological activity of synthetic [P1]PTH(1-34) was indistinguishable from that of unmodified [S1]PTH(1-34). However, in contrast to conditioned medium from COS-7 cells expressing prepro[S1]PTH(1-84), medium from cells expressing prepro[P1]PTH(1-84) failed to stimulate cAMP production despite similar PTH levels when measured by an intact assay that detects PTH(1-84) and large amino-terminally truncated fragments thereof. Analysis of the secreted, but inactive PTH variant led to the identification of pro[P1]PTH(−6 to +84). Synthetic pro[P1]PTH(−6 to +34) and pro[S1]PTH(−6 to +34) had much less bioactivity than the corresponding PTH(1-34) analogs. Unlike pro[S1]PTH(−6 to +34), pro[P1]PTH(−6 to +34) was resistant to cleavage by furin suggesting that the amino acid variant impairs preproPTH processing. Consistent with this conclusion, plasma of patients with the homozygous P1 mutation had elevated proPTH levels, as determined with an in-house assay specific for pro[P1]PTH(−6 to +84). In fact, a large fraction of PTH detected by the commercial intact assay represented the secreted pro[P1]PTH. In contrast, two commercial biointact assays that use antibodies directed against the first few amino acid residues of PTH(1-84) for capture or detection failed to detect pro[P1]PTH.

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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