Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature

Hum Mutat. 2015 Apr;36(4):474-81. doi: 10.1002/humu.22773. Epub 2015 Mar 16.


Based on the observation of reduced stature in relatives of patients with acromesomelic dysplasia, Maroteaux type (AMDM), caused by homozygous or compound heterozygous mutations in natriuretic peptide receptor-B gene (NPR2), it has been suggested that heterozygous mutations in this gene could be responsible for the growth impairment observed in some cases of idiopathic short stature (ISS). We enrolled 192 unrelated patients with short stature and 192 controls of normal height and identified seven heterozygous NPR2 missense or splice site mutations all in the short stature patients, including one de novo splice site variant. Three of the six inherited variants segregated with short stature in the family. Nine additional rare nonsynonymous NPR2 variants were found in three additional cohorts. Functional studies identified eight loss-of-function mutations in short individuals and one gain-of-function mutation in tall individuals. With these data, we were able to rigorously verify that NPR2 functional haploinsufficiency contributes to short stature. We estimate a prevalence of NPR2 haploinsufficiency of between 0 and 1/26 in people with ISS. We suggest that NPR2 gain of function may be a more common cause of tall stature than previously recognized.

Keywords: ISS; NPR2; natriuretic peptide receptor-B; short stature.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Child
  • Child, Preschool
  • Dwarfism / diagnosis*
  • Dwarfism / genetics*
  • Female
  • Gene Frequency
  • Genetic Association Studies
  • Genetic Variation
  • Heterozygote*
  • Humans
  • Male
  • Mutation*
  • Pedigree
  • Phenotype*
  • Receptors, Atrial Natriuretic Factor / genetics*
  • Receptors, Atrial Natriuretic Factor / metabolism
  • Sequence Analysis, DNA


  • Receptors, Atrial Natriuretic Factor
  • atrial natriuretic factor receptor B