A Form of Jansen’s Metaphyseal Chondrodysplasia with Limited Metabolic and Skeletal Abnormalities Is Caused by a Novel Activating Parathyroid Hormone (PTH)/PTH-Related Peptide Receptor Mutation

Abstract

A novel heterozygous PTH/PTHrP receptor missense mutation (T410R) was identified in a male and his two sons who are all affected by a less severe form of Jansen's metaphyseal chondrodysplasia (JMC). JMC is a rare disorder that is typically characterized by severe growth plate abnormalities that lead to short-limbed dwarfism. Furthermore, affected individuals usually show significant hypercalcemia, despite normal or undetectable levels of PTH and PTHrP. In contrast, the three affected members of this new family showed only mild skeletal dysplasia, comparatively normal stature, and blood calcium concentrations either within or at the upper end of the normal range. However, PTH levels were suppressed, and urinary calcium excretion was elevated, which led to nephrolithiasis in both children. When expressed in COS-7 cells, the PTH/PTHrP receptor with the T410R mutation led to agonist-independent cAMP formation, which was less pronounced than that observed with the previously identified T410P mutant. Our findings indicate that a mild form of JMC has been identified that is characterized by less pronounced skeletal and laboratory abnormalities.

PTH Stimulated Growth and Decreased Col‐X Deposition are Phosphotidylinositol‐3,4,5 Triphosphate Kinase and Mitogen Activating Protein Kinase Dependent in Avian Sterna

“…A single copy mutation may result in Jansen's metaphyseal chondrodysplasia (JMC). JMC is a rare autosomal dominant form of short limb dwarfism characterized by asymptomatic hypercalcemia and skeletal deformities, with low PTH and PTHrP levels (Minagawa et al, 1997;Schipani and Provot, 2003;Bastepe et al, 2004). This rare disorder may be caused by activating mutations in the PTH/PTHrP receptor leading to ligandindependent cAMP accumulation.…”

Antihistaminergics and inverse agonism: Potential therapeutic applications

“…In these circumstances, the underlying condition may be only effectively treated with inverse agonists. Mutations, which may be preserved in the germ line, have been shown to occur in GPCRs and result in constitutive receptor activity in patients with clinical syndromes, such as Jansen's metaphyseal condrodysplasia or congenital hyperthtyroidism (Bastepe et al, 2004;Davies et al, 2005;Seifert and Wenzel-Seifert, 2002). Most of these diseases are associated with the endocrine system, although visual alterations due to rhodopsin mutations (Dryja et al, 1993;Keen et al, 1991) and some viral infections were also related to constitutively active forms of GPCRs (Arvanitakis et al, 1997;Fitzsimons et al, 2006;Maussang et al, 2009).…”

Skull Base and Cervical Spine Involvement in Jansen Syndrome: Case Report

“…The JMD gene has been localized to the 3p22-p21.1 chromosome, which is the parathyroid hormone-related peptide receptor ( PTHR1 ). Four distinct mutations in the PTHR1 gene have been recognized including His223Arg, Thr410Pro, Ile458Argw, and Thr410Arg [6,[18][19][20] . Genetic analysis and counseling can be of possible benefit for the affected individuals and their families as the treatment for this disorder has largely been symptomatic and supportive.…”