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.