Rare PTH Gene Mutations Causing Parathyroid Disorders: A Review

Abstract

Since parathyroid hormone (PTH) was first isolated and its gene (PTH) was sequenced, only eight PTH mutations have been discovered. The C18R mutation in PTH, discovered in 1990, was the first to be reported. This autosomal dominant mutation induces endoplasmic reticulum stress and subsequent apoptosis in parathyroid cells. The next mutation, which was reported in 1992, is associatedwith exon skipping. The substitution of G with C in the first nucleotide of the second intron results in the exclusion of the secondexon; since this exon includes the initiation codon, translation initiation is prevented. An S23P mutation and an S23X mutation at thesame residue were reported in 1999 and 2012, respectively. Both mutations resulted in hypoparathyroidism. In 2008, a somaticR83X mutation was detected in a parathyroid adenoma tissue sample collected from a patient with hyperparathyroidism. In 2013, aheterozygous p.Met1_Asp6del mutation was incidentally discovered in a case-control study. Two years later, the R56C mutation wasreported; this is the only reported hypoparathyroidism-causing mutation in the mature bioactive part of PTH. In 2017, another heterozygous mutation, M14K, was detected. The discovery of these eight mutations in the PTH gene has provided insights into itsfunction and broadened our understanding of the molecular mechanisms underlying mutation progression. Further attempts to detectother such mutations will help elucidate the functions of PTH in a more sophisticated manner.