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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(\u22126 to\u00a0+84). Synthetic pro[P1]PTH(\u22126 to\u00a0+34) and pro[S1]PTH(\u22126 to\u00a0+34) had much less bioactivity than the corresponding PTH(1-34) analogs. Unlike pro[S1]PTH(\u22126 to\u00a0+34), pro[P1]PTH(\u22126 to\u00a0+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(\u22126 to\u00a0+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.<\/jats:p>","DOI":"10.1073\/pnas.2208047120","type":"journal-article","created":{"date-parts":[[2023,2,16]],"date-time":"2023-02-16T13:47:49Z","timestamp":1676555269000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":6,"title":["Homozygous Ser-1 to Pro-1 mutation in parathyroid hormone identified in hypocalcemic patients results in secretion of a biologically inactive pro-hormone"],"prefix":"10.1073","volume":"120","author":[{"given":"Patrick","family":"Hanna","sequence":"first","affiliation":[{"name":"Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashok","family":"Khatri","sequence":"additional","affiliation":[{"name":"Endocrine Unit, 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