Chapter 36 - Genetic Disorders Caused by Mutations in the PTH/PTHrP Receptor, its Ligands, and Downstream Effector Molecules

Abstract

The PTH/PTHrP receptor (PTH1R; gene name, PTH1R) is a G protein-coupled receptor (GPCR) that 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). Because of these dual actions, the PTH1R has several different biological functions, including the PTH-dependent regulation of mineral ion homeostasis and bone metabolism, and the PTHrP-dependent regulation of bone elongation. Consequently, genetic mutations in the genes encoding PTH, PTHrP, PTH1R, and some of the target proteins downstream of the PTH1R can lead to major developmental or regulatory abnormalities. Mutations in genes other than PTH can cause isolated hypoparathyroidism (IHP); these include GCM2, which encodes a parathyroid-specific transcription factor, and GNA11, which encodes one of the signaling proteins at the calcium-sensing receptor (CaSR), respectively. In contrast, mutations in PTHLH or PTH1R lead to different forms of chondrodysplasia, including Jansen’s metaphyseal chondrodysplasia (JMC), Blomstrand’s lethal chondrodysplasia (BLC), Eiken familial skeletal dysplasia, and brachydactyly. Some forms of enchondromatosis (Ollier’s disease) are also caused by PTH1R mutations, but most patients affected by Ollier’s and the related Maffucci disease carry mutations in IDH1 and IDH2, the genes encoding isocitrate dehydrogenases. Delayed tooth eruption can be caused by several different heterozygous mutations involving PTH1R or GNAS. Heterozygous mutations in those GNAS exons that encode the alpha-subunit of the stimulatory G protein (Gsα) downstream of the PTH1R (and numerous other GPCRs) cause pseudohypoparathyroidism type Ia (PHP1A), while the same or similar mutations on the paternal allele lead to pseudopseudohypoparathyroidism (PPHP). In contrast, the autosomal dominant forms of pseudohypoparathyroidism type Ib (PHP1B) are caused by different microdeletions within or upstream of the GNAS complex locus, which are associated with loss-of-methylation at one or several differentially methylated regions within the GNAS complex locus. Heterozygous mutations in PRKAR1A, the gene encoding the regulatory subunit of protein kinase A downstream of the adenylate cyclase, cause a form of acrodysostosis that is associated with resistance to several hormones, which signal through GPCRs (ACRDYS1 or ADOHR), while mutations in the cAMP-specific phosphodiesterase PDE4D lead to acrodysostosis with or without hormonal abnormalities (ACRDYS2 or ADOP4). Heterozygous HDAC4 mutations have been identified in the brachydactyly mental retardation syndrome (BDMR). The molecular definition of rare human disorders thus has provided important novel insights into the regulation of mineral ion homeostasis and bone formation.