Autosomal Dominant PTH Gene Signal Sequence Mutation in a Family With Familial Isolated Hypoparathyroidism

Luigia Cinque, Angelo Sparaneo, Laura Penta, Amedea Mencarelli, Daniela Rogaia, Susanna Esposito, Federico Pio Fabrizio, Filomena Baorda, Alberto Verrotti, Alberto Falorni, Gabriela Stangoni, Geoffrey N. Hendy, Vito Guarnieri, Paolo Prontera

Research output: Contribution to journalArticlepeer-review


Context: Familial isolated hypoparathyroidism (FIH) is a genetically heterogeneous disorder due to mutations of the calcium-sensing receptor (CASR), glial cells missing-2 (GCM2), guanine nucleotide binding protein α11 (GNA11), or parathyroid hormone (PTH) genes. Thus far, only four cases with homozygous and two cases with heterozygous mutations in the PTH gene have been reported.

Objective: To clinically describe an FIH family and identify and characterize the causal gene mutation.

Design: Genomic DNA of the family members was subjected to CASR, GCM2, GNA11, and PTH gene mutational analysis. Functional assays were performed on the variant identified.

Participants: Six subjects of a three-generation FIH family with three affected individuals having severe hypocalcemia and inappropriately low serum PTH.

Results: No mutations were detected in the CASR, GCM2, and GNA11 genes. A heterozygous variant that segregated with the disease was identified in PTH gene exon 2 (c.41T>A; p.M14K). This missense variant, in the hydrophobic core of the signal sequence, was predicted in silico to impair cleavage of preproPTH to proPTH. Functional assays in HEK293 cells demonstrated much greater retention intracellularly but impaired secretion into the medium of the M14K mutant relative to wild type. The addition of the pharmacological chaperone, 4-phenylbutyric acid, led to a reduction of cellular retention and increased accumulation in the cell medium of the M14K mutant.

Conclusions: We report a heterozygous PTH mutation in an FIH family and demonstrate accumulation of the mutant intracellularly and its impaired secretion. An accurate genetic diagnosis in such hypoparathyroid patients is critical for appropriate treatment and genetic counseling.

Original languageEnglish
Pages (from-to)3961-3969
Number of pages9
JournalThe Journal of clinical endocrinology and metabolism
Issue number11
Publication statusPublished - Nov 1 2017

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical


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