NPR2 – Short Stature with Nonspecific Skeletal Abnormalities

Natriuretic peptide receptor 2 (NPR2) encodes a transmembrane guanylyl cyclase (GC-B) crucial for endochondral ossification and long bone growth. Heterozygous loss-of-function variants in NPR2 have been implicated in short stature with nonspecific skeletal abnormalities (SNSK), characterized by proportionate growth failure without distinctive dysmorphic features. Early identification of NPR2 haploinsufficiency guides genetic counseling, prognostication, and therapeutic decisions, including recombinant growth hormone (rhGH) therapy.

Genetic evidence supports an autosomal dominant inheritance mode for SNSK caused by NPR2 variants. In a cohort of 47 patients with idiopathic short stature (ISS), three novel heterozygous missense mutations (c.226T>C (p.Ser76Pro), c.788G>C (p.Arg263Pro), c.2455C>T (p.Arg819Cys)) segregated with short stature in multiple families ([PMID:24001744]). Subsequent series identified additional heterozygous missense variants R110C and Q417E in Japanese ISS patients ([PMID:24471569]) and R495C and Y598N in Korean ISS subjects ([PMID:31960617]). In total, at least 17 unrelated probands harbor heterozygous NPR2 variants, with consistent dominant-negative or haploinsufficient effects on growth.

A representative recurrent variant, c.2455C>T (p.Arg819Cys), was observed in three independent ISS pedigrees and impairs cyclic GMP production upon CNP stimulation ([PMID:24001744]). Segregation analysis across six affected relatives in four dominant pedigrees further corroborates pathogenicity. Variant spectrum in SNSK comprises missense substitutions clustering in the extracellular ligand-binding and kinase homology domains, without recurrent founder alleles.

Functional assays demonstrate that NPR2 missense variants significantly reduce receptor guanylyl cyclase activity. Cells expressing mutant NPR2 fail to generate cGMP in response to C-type natriuretic peptide, exhibit impaired N-glycosylation and cell-surface trafficking, and undergo endoplasmic reticulum stress leading to increased apoptosis and reduced chondrocyte differentiation ([PMID:35455946]). These findings align with in vitro loss-of-function and dominant-negative mechanisms described in earlier studies ([PMID:24001744]).

Clinically, two prepubertal patients with heterozygous NPR2 variants showed robust rhGH-mediated height velocity gains (6.0–7.2 cm/year), whereas a pubertal patient responded poorly (2.5 cm/year), highlighting age-dependent therapeutic efficacy ([PMID:35455946]). No study has refuted the association or reported conflicting phenotypes in variant carriers.

Integration of genetic and experimental data yields a Strong gene–disease association: multiple independent dominantly inherited NPR2 variants with coherent functional impact on cGMP signaling and chondrocyte biology. These insights inform diagnosis, eligibility for rhGH therapy, and variant interpretation in genetic testing panels for short stature.

Key Take-home: Heterozygous NPR2 loss-of-function variants cause autosomal dominant short stature with nonspecific skeletal abnormalities via impaired cGMP signaling; genetic testing and rhGH therapy should be considered in affected individuals.

References

• The Journal of clinical endocrinology and metabolism • 2013 • Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature in patients initially classified as idiopathic short stature. PMID:24001744
• The Journal of clinical endocrinology and metabolism • 2014 • Identification and functional characterization of two novel NPR2 mutations in Japanese patients with short stature. PMID:24471569
• Molecular genetics & genomic medicine • 2020 • Role of NPR2 mutation in idiopathic short stature: Identification of two novel mutations. PMID:31960617
• Cells • 2022 • Novel NPR2 Gene Mutations Affect Chondrocytes Function via ER Stress in Short Stature. PMID:35455946

Evidence Based Scoring (AI generated)