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Identification of NPR2 gene mutations affecting chondrocyte differentiation in short stature through JAK2-STAT5

Shuoshuo Wei1,2, Mingming He1,3, Chuanpeng Zhang2

  • 1Department of Endocrinology, Genetics and Metabolism, Affiliated Hospital of Jining Medical University, Jining Medical University, 89 Guhuai Road, Jining, 272029, Shandong, People's Republic of China.

Orphanet Journal of Rare Diseases
|August 1, 2025
PubMed
Abstract

Insights

Mutations in the natriuretic peptide receptor 2 (NPR2) gene cause short stature by disrupting chondrocyte differentiation. Recombinant human growth hormone (rhGH) treatment showed efficacy in affected patients.

Area of Science:

  • Genetics
  • Molecular Biology
  • Endocrinology

Background:

  • Natriuretic peptide receptor 2 (NPR2) is vital for endochondral bone growth.
  • NPR2 gene mutations present diverse clinical phenotypes and unclear pathogenic mechanisms.
  • Limited data exists on treatment efficacy for NPR2-related skeletal disorders.

Purpose of the Study:

  • To analyze clinical phenotypes and treatment outcomes in patients with NPR2 gene mutations.
  • To elucidate the pathogenic molecular mechanisms underlying NPR2-related short stature.
  • To investigate the functional impact of NPR2 variants on skeletal development.

Main Methods:

  • Exome sequencing identified NPR2 gene mutations in three Chinese Han patients with short stature.
  • Clinical data, treatment follow-up, and family validation were collected.
  • In vitro functional assays, protein 3D structure prediction, and transcriptome sequencing were performed.

Main Results:

  • NPR2 mutations (p.R318W, p.I908T, p.R976H) caused short stature and skeletal dysplasia.
  • Mutant NPR2 showed reduced protein expression and impaired cyclic guanosine monophosphate (cGMP) production.
  • NPR2 mutations downregulated Csf2, affecting the JAK2-STAT5 pathway and chondrocyte differentiation markers (Sox9, Col2A1, BMP4).

Conclusions:

  • NPR2 gene mutations lead to short stature through a loss-of-function mechanism.
  • Downregulation of Csf2 by NPR2 mutations impacts the JAK2-STAT5 pathway and chondrocyte differentiation.
  • Recombinant human growth hormone (rhGH) demonstrated good treatment efficacy in affected patients.
Keywords:
Chondrocyte differentiationJAK2-STAT5NPR2Recombinant human growth hormoneShort stature

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