An overgrowth disorder associated with excessive production of cGMP due to a gain-of-function mutation of the natriuretic peptide receptor 2 gene

PLoS One. 2012;7(8):e42180. doi: 10.1371/journal.pone.0042180. Epub 2012 Aug 3.


We describe a three-generation family with tall stature, scoliosis and macrodactyly of the great toes and a heterozygous p.Val883Met mutation in Npr2, the gene that encodes the CNP receptor NPR2 (natriuretic peptide receptor 2). When expressed in HEK293A cells, the mutant Npr2 cDNA generated intracellular cGMP (cyclic guanosine monophosphate) in the absence of CNP ligand. In the presence of CNP, cGMP production was greater in cells that had been transfected with the mutant Npr2 cDNA compared to wild-type cDNA. Transgenic mice in which the mutant Npr2 was expressed in chondrocytes driven by the promoter and intronic enhancer of the Col11a2 gene exhibited an enhanced production of cGMP in cartilage, leading to a similar phenotype to that observed in the patients. In addition, blood cGMP concentrations were elevated in the patients. These results indicate that p.Val883Met is a constitutive active gain-of-function mutation and elevated levels of cGMP in growth plates lead to the elongation of long bones. Our findings reveal a critical role for NPR2 in skeletal growth in both humans and mice, and may provide a potential target for prevention and treatment of diseases caused by impaired production of cGMP.

Publication types

  • Case Reports
  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Amino Acid Substitution
  • Animals
  • Chondrocytes* / enzymology
  • Chondrocytes* / pathology
  • Cyclic GMP
  • DNA, Complementary
  • Fingers / abnormalities
  • Fingers / pathology
  • Gene Expression
  • Growth Disorders* / enzymology
  • Growth Disorders* / genetics
  • Growth Disorders* / pathology
  • HEK293 Cells
  • Humans
  • Limb Deformities, Congenital* / enzymology
  • Limb Deformities, Congenital* / genetics
  • Limb Deformities, Congenital* / pathology
  • Male
  • Mice
  • Mice, Transgenic
  • Mutation, Missense*
  • Receptors, Atrial Natriuretic Factor* / genetics
  • Receptors, Atrial Natriuretic Factor* / metabolism


  • DNA, Complementary
  • Receptors, Atrial Natriuretic Factor
  • atrial natriuretic factor receptor B
  • Cyclic GMP

Supplementary concepts

  • Megalodactyly

Grant support

This work was supported in part by Grants-in-aid from the Ministry of Health, Labour and Welfare of Japan [KH20Q007a-1]. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study.