Novel PTH gene mutations causing isolated hypoparathyroidism

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dc.contributor.authorHawkes, Colin P.
dc.contributor.authorAl Jubeh, Jamal M.
dc.contributor.authorLi, Dong
dc.contributor.authorTucker, Susan E.
dc.contributor.authorRajiyah, Tara
dc.contributor.authorLevine, Michael A.
dc.contributor.funderChildren's Hospital of Philadelphiaen
dc.contributor.funderNational Institutes of Healthen
dc.date.accessioned2022-02-24T09:43:45Z
dc.date.available2022-02-24T09:43:45Z
dc.date.issued2022-02-15
dc.date.updated2022-02-22T16:49:57Z
dc.description.abstractContext: PTH gene mutations represent a rare cause of familial isolated hypoparathyroidism (FIH). These defects can cause hypoparathyroidism with increased or decreased serum levels of PTH through 1) impaired PTH synthesis; 2) induction of parathyroid cell apoptosis; or 3) secretion of bioinactive PTH molecules. Eight pathogenic mutations of this gene have been described previously. Objective: Through describing two novel mutations of the PTH gene, we aim to extend the molecular basis for FIH and further refine the proposed mechanisms by which PTH mutations cause hypoparathyroidism. Design: Proband case reports with extended family analysis. Patients and Other Participants: The probands in both kindreds presented before 10-days-of-age with hypocalcemia and elevated phosphate levels. Proband A had low PTH levels, while these levels were elevated in Proband B. Proband B was initially diagnosed with pseudohypoparathyroidism. Interventions: Methylation analysis of CpG dinucleotides within three GNAS differentially methylated regions; Whole genome sequencing; and PTH infusion with analysis of nephrogenous cyclic AMP. Results: Proband A had a novel heterozygous sequence change in exon 2 of the PTH gene, c.46_47delinsAA (p.Ala16Lys) and Proband B had a novel homozygous nucleotide transition in PTH exon 3 (c.128G>A; p.G43E) that led to replacement of glycine by glutamic acid at position 12 of PTH 1-84. PTH 1-34 infusion demonstrated that renal responsiveness to PTH was intact and not antagonized by circulating bioinactive PTH. Conclusions: PTH gene mutations are uncommon causes of hypoparathyroidism, but can be misdiagnosed as disorders of gland development or receptor function if PTH levels are decreased or elevated, respectively. Genetic testing should be considered early in the diagnostic approach to these presentations.en
dc.description.sponsorshipNational Institutes of Health (R01 DK112955)en
dc.description.statusPeer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationHawkes, C. P., Al Jubeh, J. M., Li, D., Tucker, S. E., Rajiyah, T. and Levine, M. A. (2022) 'Novel PTH gene mutations causing isolated hypoparathyroidism', Journal of Clinical Endocrinology and Metabolism. doi: 10.1210/clinem/dgac086en
dc.identifier.doi10.1210/clinem/dgac086en
dc.identifier.eissn1945-7197
dc.identifier.issn0021-972X
dc.identifier.journaltitleJournal of Clinical Endocrinology and Metabolismen
dc.identifier.urihttps://hdl.handle.net/10468/12599
dc.language.isoenen
dc.publisherOxford University Pressen
dc.rights© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved.en
dc.subjectParathyroiden
dc.subjectHypoparathyroidismen
dc.subjectHypocalcemiaen
dc.subjectGeneticen
dc.subjectBioinactiveen
dc.subjectPTHen
dc.titleNovel PTH gene mutations causing isolated hypoparathyroidismen
dc.typeArticle (peer-reviewed)en
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