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J Clin Endocrinol Metab. 2017 Nov 1;102(11):3961-3969. doi: 10.1210/jc.2017-00250.

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

Author information

1
Medical Genetics and Laboratory of Oncology, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Foggia 71013, Italy.
2
Department of Pediatrics, University of Perugia, Perugia 06100, Italy.
3
Regional Reference Centre for Medical Genetics, "Santa Maria della Misericordia" Hospital, Perugia 06129, Italy.
4
Department of Paediatrics, University of L'Aquila, L'Aquila 67100, Italy.
5
Section of Internal Medicine and Endocrine and Metabolic Sciences, Department of Medicine, University of Perugia, Perugia 06100, Italy.
6
Metabolic Disorders and Complications, McGill University Health Centre Research Institute, Montreal, Quebec H4A 3J1, Canada.
7
Department of Medicine, McGill University, Montreal, Quebec H4A 3J1, Canada.
8
Department of Physiology, McGill University, Montreal, Quebec H3G 1Y6, Canada.
9
Department of Human Genetics, McGill University, Montreal, Quebec H3A 0C7, Canada.

Abstract

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.

PMID:
28938448
DOI:
10.1210/jc.2017-00250
[Indexed for MEDLINE]

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