NPR2 and Acromesomelic Dysplasia, Type Maroteaux

Abstract

Abstract A signaling pathway that is active during endochondral ossi2cation, involving C-type natriuretic peptide [CNP, gene name natriuretic peptide precursor C (NPPC)] and the natriuretic peptide receptors 2 and 3 (NPR2, NPR3) is essential for normal skeletal growth. The importance of this pathway was 2rst identi2ed in mice with naturally occurring and/or targeted mutations in NPPC and NPR3 (Jaubert et al., 1999; Matsukawa et al., 1999; Chusho et al., 2001). Humans with the autosomal recessive, skeletal dysplasia, acromesomelic dysplasia, type Maroteaux (AMDM) have NPR2 mutations, which cause a complete loss of receptor function (Bartels et al., 2004); interestingly, heterozygous NPR2 mutation carriers have no evidence of skeletal dysplasia, but are shorter than noncarriers (Bartels et al., 2004; Olney et al., 2006). The upstream and downstream participants/pathways involved in CNP/NPR2 signaling are incompletely understood, but thus far include cGMP-mediated pathways, ERK1/2 within the mitogen-activated protein kinase (MAPK) pathway and possibly the transcription factor SOX9 (Chikuda et al., 2004; Yasoda et al., 2004; Krejci et al., 2005).