Endocrinol Metab.  2020 Mar;35(1):64-70. 10.3803/EnM.2020.35.1.64.

Rare PTH Gene Mutations Causing Parathyroid Disorders: A Review

• Lee JH
• Davaatseren M
• Lee S

• KMID: 2471721
• DOI: http://doi.org/10.3803/EnM.2020.35.1.64

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 associated with exon skipping. The substitution of G with C in the first nucleotide of the second intron results in the exclusion of the second exon; since this exon includes the initiation codon, translation initiation is prevented. An S23P mutation and an S23X mutation at the same residue were reported in 1999 and 2012, respectively. Both mutations resulted in hypoparathyroidism. In 2008, a somatic R83X mutation was detected in a parathyroid adenoma tissue sample collected from a patient with hyperparathyroidism. In 2013, a heterozygous p.Met1_Asp6del mutation was incidentally discovered in a case-control study. Two years later, the R56C mutation was reported; 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 its function and broadened our understanding of the molecular mechanisms underlying mutation progression. Further attempts to detect other such mutations will help elucidate the functions of PTH in a more sophisticated manner.

Keyword

Parathyroid glands; Genes; Mutation; Parathyroid hormone; Hypoparathyroidism; Hyperparathyroidism

MeSH Terms

Apoptosis
Case-Control Studies
Codon, Initiator
Endoplasmic Reticulum Stress
Exons
Humans
Hyperparathyroidism
Hypoparathyroidism
Introns
Parathyroid Diseases*
Parathyroid Glands
Parathyroid Hormone
Parathyroid Neoplasms
Codon, Initiator
Parathyroid Hormone

Figure

• 

  Fig. 1 (A) Primary sequence of human parathyroid hormone (PTH) and organization of its domains. The pre- (signal sequence), pro- (black box), and mature regions (boxed) of PTH are labeled. The first six amino acids in the signal sequence are deleted in a patient with hypoparathyroidism. The arrowheads indicate the wild-type amino acids in pre-pro-PTH that are replaced by mutant amino acids or terminated. (B) Schematic presentation of the human parathyroid hormone (PTH) gene, which consists of three exons and two introns. The G to C nucleotide change at the beginning of intron 2 results in exon 2 being skipped in patients with autosomal dominant familial hypoparathyroidism; [reference], see references for details [8].

• 

  Fig. 2 (A) Illustration of parathyroid hormone (PTH) synthesis and secretion from chief cells of parathyroid glands. In each step, pathophysiological explanations are noted with x mark. (B) Signal transduction pathways from the activated PTH receptor from its respective target tissues, i.e., bone and kidney. Note that differences in signal transduction pathways activated by either wild type PTH or Cys25PTH(1-84) are still to be investigated. Adapted from Hammer et al. [17], with permission from McGraw-Hill Education. CaR, calcium-sensing receptor; AC adenylate cyclase; PTH-R, PTH receptor; G, G protein; Gs, Gs alpha subunit; PLC, phospholipase C; PIP2, phosphatidylinositol 4,5-bisphosphate; ATP, adenosine triphosphate; AMP, adenosine monophosphate.

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