Novel PTH Gene Mutations Causing Isolated Hypoparathyroidism.

Area of Science:

• Endocrinology
• Genetics
• Molecular Biology

Background:

• Familial isolated hypoparathyroidism (FIH) is a rare genetic disorder.
• Mutations in the parathyroid hormone (PTH) gene are an infrequent cause of FIH.
• Known PTH gene defects lead to hypoparathyroidism via impaired synthesis, apoptosis, or secretion of inactive PTH.

Purpose of the Study:

• To describe two novel mutations in the PTH gene.
• To expand the understanding of the molecular basis for FIH.
• To further elucidate the mechanisms by which PTH mutations cause hypoparathyroidism.

Main Methods:

• Case reports and family analysis of two kindreds.
• Whole-genome sequencing and methylation analysis of GNAS differentially methylated regions.
• Parathyroid hormone (PTH) infusion tests to assess renal responsiveness.

Main Results:

• Identified a novel heterozygous mutation (c.46_47delinsAA) in Proband A, presenting with low PTH.
• Identified a novel homozygous mutation (c.128G > A) in Proband B, presenting with elevated PTH and initially misdiagnosed.
• PTH infusion confirmed intact renal responsiveness in Proband B, ruling out receptor antagonism.

Conclusions:

• PTH gene mutations are rare but important causes of hypoparathyroidism.
• These mutations can be misdiagnosed if PTH levels are not interpreted alongside genetic findings.
• Genetic testing should be considered early in the diagnostic workup for suspected FIH.