Novel Pathogenic NPR2 Variants in Short Stature Patients and the Therapeutic Response to rhGH

Abstract

Abstract Objective A heterozygous loss-of-function mutation in the NPR2 gene causes short stature with non-specific skeletal abnormalities, accounting for approximately 2 ~ 6% of all idiopathic short stature cases. The aim of this study was to analyze and identify pathogenic variants in the NPR2 gene, and to examine the therapeutic response to recombinant growth hormone (rhGH). Methods NPR2 was sequenced in three Chinese Han patients with short stature via whole-exome sequencing. In vitro functional experiments, homology modeling, and molecular docking analysis of variants were conducted to investigate putative protein changes and pathogenicity. Three patients received rhGH therapy for two years. Result Two NPR2 heterozygous variants were identified: c.1579C > T,p.Leu527Phe in patient 1 and c.2842dupC,p.His948Profs*5 in patient 2. A small gene model was constructed, and transcriptional analysis of the synonymous mutation (c.2643G > A) was performed in patient 3, which revealed the deletion of exon 17 and the premature formation of a stop codon (p.His840Gln*). Functional studies showed that both NPR2 variants, His948Profs*5 and His840Gln*, failed to produce cGMP in the homozygous state. Furthermore, the Leu527Phe variant of NPR2 was almost unresponsive to the stimulatory effect of ATP on CNP-dependent guanylyl cyclase activity. This loss of response to ATP has not been previously reported. The average age of patients at the start of treatment was about 6.5 ± 1.8 years old, and their height increased by 1.59 ± 0.1 SDS after 2 years of treatment. Conclusion we report 2 cases of novel pathogenic mutations in the NPR2 gene. We broadened the genotypic spectrum of NPR2 variants in short stature patients and provided insights into rhGH's efficacy.