Novel pathogenic NPR2 variants in short stature patients and the therapeutic response to rhGH

Abstract

AbstractObjectiveHeterozygous loss-of-function variants in theNPR2gene cause short stature with nonspecific skeletal abnormalities and account for about 2 ~ 6% of idiopathic short stature. This study aimed to analyze and identify pathogenic variants in theNPR2gene and explore the therapeutic response to recombinant growth hormone (rhGH).MethodsNPR2was sequenced in three Chinese Han patients with short stature via exome sequencing. In vitro functional experiments, homology modeling and molecular docking analysis of variants were performed to examine putative protein changes and the pathogenicity of the variants.ResultThree patients received rhGH therapy for two years, and twoNPR2heterozygous variants were identified in three unrelated cases: c.1579 C > T,p.Leu527Phe in patient 1 and c.2842dupC,p.His948Profs*5 in patient 2. Subsequently, a small gene model was constructed, and transcriptional analysis of the synonymous variant (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 6.5 ± 1.8 years old, and their height increased by 1.59 ± 0.1 standard deviation score after 2 years of treatment.ConclusionIn this report, two novel variants inNPR2gene were described. Our findings broaden the genotypic spectrum ofNPR2variants in individuals with short stature and provid insights into the efficacy of rhGH in these patients.