A novel loss-of-function mutation in Npr2 clarifies primary role in female reproduction and reveals a potential therapy for acromesomelic dysplasia, Maroteaux type

Hum Mol Genet. 2013 Jan 15;22(2):345-57. doi: 10.1093/hmg/dds432. Epub 2012 Oct 12.


We discovered a new spontaneous mutant allele of Npr2 named peewee (pwe) that exhibits severe disproportionate dwarfism and female infertility. The pwe phenotype is caused by a four base-pair deletion in exon 3 that generates a premature stop codon at codon 313 (L313X). The Npr2(pwe/pwe) mouse is a model for the human skeletal dysplasia acromesomelic dysplasia, Maroteaux type (AMDM). We conducted a thorough analysis of the female reproductive tract and report that the primary cause of Npr2(pwe/pwe) female infertility is premature oocyte meiotic resumption, while the pituitary and uterus appear to be normal. Npr2 is expressed in chondrocytes and osteoblasts. We determined that the loss of Npr2 causes a reduction in the hypertrophic and proliferative zones of the growth plate, but mineralization of skeletal elements is normal. Mutant tibiae have increased levels of the activated form of ERK1/2, consistent with the idea that natriuretic peptide receptor type 2 (NPR2) signaling inhibits the activation of the MEK/ERK mitogen activated protein kinase pathway. Treatment of fetal tibiae explants with mitogen activated protein kinase 1 and 2 inhibitors U0126 and PD325901 rescues the Npr2(pwe/pwe) growth defect, providing a promising foundation for skeletal dysplasia therapeutics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Bone Density / genetics
  • Bone Diseases, Developmental / drug therapy
  • Bone Diseases, Developmental / genetics*
  • Bone and Bones / metabolism
  • Dwarfism / genetics
  • Female
  • Genotype
  • Humans
  • Infertility, Female / genetics
  • MAP Kinase Signaling System / drug effects
  • Male
  • Mice
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Mutation*
  • Phenotype
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / pharmacology
  • Receptors, Atrial Natriuretic Factor / genetics*
  • Reproduction / genetics*


  • Protein Kinase Inhibitors
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Receptors, Atrial Natriuretic Factor
  • atrial natriuretic factor receptor B

Supplementary concepts

  • Acromesomelic dysplasia, Maroteaux type