Overgrowth syndrome associated with a gain‐of‐function mutation of the natriuretic peptide receptor 2 (NPR2) gene

Abstract

The signal pathway of the C-type natriuretic (CNP) and its receptor, natriuretic peptide receptor 2 (NPR2) is involved in the longitudinal growth of long bones. Loss of function mutations at NPR2 cause acromesomelic dysplasia, type Maroteaux, while overproduction of CNP by chromosomal translocation and a gain-of-function mutation at NPR2 have been reported to be responsible for an overgrowth syndrome in three cases and one family, respectively. We identified a four-generation family with an overgrowth syndrome characterized by tall stature, macrodactyly of the great toes, scoliosis, coxa valga and slipped capital femoral epiphysis, similar to those previously reported in association with CNP/NPR2 overactivity. The serum level of amino-terminal proCNP was normal in the proband. A novel missense mutation of NPR2, c.1462G>C (p.Ala488Pro) was found to co-segregate with the phenotype in this family. In vitro transfection assay of the mutant NPR2 revealed overactivity of the mutant receptor at baseline as well as with the ligand. This overgrowth syndrome caused by a gain-of-function mutation at NPR2 should be differentiated from Marfan or related syndromes, and may be categorized along with the overgrowth syndrome caused by overproduction of CNP due to its phenotypical similarity as overgrowth CNP/NPR2 signalopathy.

Fibroblast growth factor signaling in skeletal development and disease

“…Mice or humans that overexpress CNP or activate natriuretic peptide receptor 2 (Npr2; guanylyl cyclase B) have a skeletal overgrowth phenotype ( Fig. 2; Yasoda et al 2004;Bocciardi et al 2007;Hannema et al 2013;Miura et al 2014), while mice that lack CNP (Nppc −/− ) or humans with heterozygous mutations in NPR2 exhibit skeletal dwarfism (Tsuji and Kunieda 2005;Nakao et al 2015).…”

Circulating osteocrin stimulates bone growth by limiting C-type natriuretic peptide clearance

“…In addition, heterozygous loss-offunction mutations of NPR-B have been reported to cause short stature and mild skeletal defects (11)(12)(13)(14)(15), and recently heterozygous loss-of-function mutations of CNP have also been shown to cause similar skeletal defects to those of NPR-B (16). Furthermore, a recent case series showed that gain-of-function mutations in NPR-B cause a skeletal overgrowth phenotype (17,18), demonstrating the ability of CNP/NPR-B signaling to stimulate bone growth in humans. On the other hand, natriuretic peptide clearance receptor (NPR-C), which lacks the intracellular domain of the receptor, is thought to be engaged in clearing natriuretic peptide ligands.…”

Homozygous Sequence Variants in the NPR2 Gene Underlying Acromesomelic Dysplasia Maroteaux Type (AMDM) in Consanguineous Families

“…To date, 32 functional sequence variants, including 25 associated with AMDM, in the NPR2 gene have been reported (Bartels et al, 2004;Olney, 2006;Hachiya et al, 2007;Khan et al, 2012). Four other sequence variants in the gene resulted in nonsyndromic short stature (Vasques et al, 2013;Amano et al, 2014) and three in overgrowth syndromes (Miura et al, 2012;Hannema et al, 2013;Miura et al, 2014).…”