Harald Jüppner

Genetic Disorders Affecting PTH/PTHrP Receptor Function

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.

PARATHYROID HORMONE BIOSYNTHESIS AND ACTION: Molecular Analysis Of the Parathyroid Hormone Gene and Parathyroid Hormone/Parathyroid Hormone-Related Peptide Receptor

Publisher Summary This chapter discusses the molecular analysis of the parathyroid hormone (PTH) gene and parathyroid hormone-related peptide receptor (PTHrP). The human PTH gene is a single-copy gene that extends over 4200 basepairs of DNA on the short arm of chromosome 11. The gene contains three exons, the first of which is noncoding. The second exon contains the initiator ATG and encodes all of the signal or pre-sequence and most of the short pro-peptide. The third exon encodes the remainder of the pro-sequence, the residues corresponding to the mature hormone, as well as the 3′ noncoding region. PTH/PTHrP receptors from marsupial kidney and from kidney and bone of two mammalian species, human and rat, are highly homologous. PTH and PTHrP bind with equal affinity to similar, perhaps identical, receptors in kidney and bone. PTH/PTHrP receptors stimulate adenylate cyclase with the same efficacy when activated by either ligand or are capable of activating at least two effector molecules, adenylate cyclase and phospholipase C. PTH/PTHrP receptors have significant homology only with the calcitonin and the secretin receptor and little or no similarities with other G protein-linked receptors. These three receptor types represent the first members of a novel family of G protein-linked receptors.