Volume 21, Issue 2, June 2005

Table of Contents 21-2

The Many Faces of PTHR1 Mutations

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Gain-of-function mutations of the gene encoding the parathyroid hormone (PTH)/PTH-related peptide (PTHrP) type 1 receptor (PTHR1)gene cause the severe, dominantly inherited metaphyseal chondrodysplasia, type Jansen. Loss-of function mutations of this receptor are associated with osteosclerosis and advanced skeletal maturation of the recessively inherited Blomstrand chondrodysplasia. Eiken syndrome is a rare autosomal recessive bone dysplasia with a skeletal phenotype quite different from the other 2 conditions, most notably exhibiting multiple epiphyseal dysplasia with extremely delayed ossification.

Duchatelet et al mapped Eiken syndrome in an informative family to the region PTHR1 locus. Mutation analysis revealed an ARG485STOP nonsense mutation in the last exon that predicts truncation of the last 108 amino acids from the receptor’s cytoplasmic tail. This domain contains several elements critical to the function of the receptor. These include several serine residues that are phosphorylated upon ligand binding and docking sites for proteins that propagate PTHR1 signals including G-protein receptor kinases (ie, adenyl cyclase(AC)/protein kinase A (PKA), phospholipase C (PLC), protein kinase C (PKC)) and ß-arrestin as well as residues that participate in the receptor internalization and down regulation.

The authors did not carry out functional studies, but they speculated based on what has been previously reported from knockin mouse and cell culture investigations in which the receptor was genetically modified to alter kinase-mediated signaling pathways. Specifically, they propose that the truncation creates an imbalance between AC/PKA versus PLC/PKA activation. They acknowledge that other mechanisms could be involved.

Duchatelet S, Ostergaard E, Cortes D, Lemaninque A, Julier C. Recessive mutations in PTHR1cause contrasting skeletal dysplasias in Eiken and Blomstrand syndromes. Hum Molec Genet. 2005;14:1-5.

Editor’s Comment: This is an interesting paper, not so much because of any firm conclusions about the mechanism involved since the authors provide no biological data; rather, it is because there are 3 distinct clinical phenotypes associated with mutations of the same gene. This study underscores the fact that many proteins have multiple functions that reflect different domains of the protein and that mutations of genes encoding these proteins can have quite different consequences depending upon which of these domain functions they disturb.

William A. Horton, MD

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