Chapter 28 - Genetic Disorders Affecting PTH/PTHrP Receptor Function

Abstract

The PTH/PTHrP receptor (PTH1R; gene name, PTH1R ) mediates the actions of parathyroid hormone (PTH; gene name, PTH ) and PTH-related peptide (PTHrP, also referred to as PTH-like peptide, PTHLP; gene name, PTHLH ), and thus has a critical role in the regulation of mineral ion homeostasis and bone metabolism, and bone elongation. Consequently, genetic mutations in the genes encoding PTH, PTHrP, PTH1R, or some of the target proteins downstream of the PTH1R can lead to major developmental or regulatory abnormalities. Mutations in PTH or the parathyroid-specific transcription factor GCMB are a rare cause of isolated hypoparathyroidism, while mutations in PTHLH or PTH1R lead to different forms of chondrodysplasia, including Jansen’s metaphyseal chondrodysplasia (JMC), Blomstrand’s lethal chondrodysplasia (BLC), and Eiken familial skeletal dysplasia. Furthermore, some forms of enchondromatosis (Ollier’s disease) and familial forms of delayed tooth eruption appear to be caused by heterozygous mutations in this G protein-coupled receptor (GPCR). Maternally and paternally inherited, inactivating mutations in the alpha-subunit of the stimulatory G protein (Gsα) downstream of numerous GPCRs, including the PTH1R, are the cause of pseudohypoparathyroidism type Ia (PHP-Ia) and pseudopseudohypoparathyroidism (PPHP), respectively, while the autosomal dominant form of pseudohypoparathyroidism type Ib (PHP-Ib) is caused by several different microdeletions within or upstream of the GNAS locus, which encodes Gsα. A recurrent heterozygous mutation in PRKAR1A , the gene encoding the regulatory subunit of protein kinase A downstream of the adenylate cyclase, is the cause of a form of acrodysostosis which is associated with resistance to several hormones that signal through different GPCRs. Furthermore, heterozygous HDAC4 mutations are the cause of brachydactyly mental retardation syndrome (BDMR). The molecular definition of these rare human disorders has provided novel insights into the regulation of mineral ion homeostasis and bone formation.