Novel pathogenic NPR2 variants in short stature patients and the therapeutic response to rhGH
Abstract Objective Heterozygous loss-of-function variants in the NPR2 gene 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 the NPR2 gene and explore the therapeutic r...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-07-01
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| Series: | Orphanet Journal of Rare Diseases |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13023-023-02757-8 |
| _version_ | 1797769290626105344 |
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| author | Hong Chen Suping Zhang Yunteng Sun Jiao Chen Ke Yuan Ying Zhang Xiaohong Yang Xiangquan Lin Ruimin Chen |
| author_facet | Hong Chen Suping Zhang Yunteng Sun Jiao Chen Ke Yuan Ying Zhang Xiaohong Yang Xiangquan Lin Ruimin Chen |
| author_sort | Hong Chen |
| collection | DOAJ |
| description | Abstract Objective Heterozygous loss-of-function variants in the NPR2 gene 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 the NPR2 gene and explore the therapeutic response to recombinant growth hormone (rhGH). Methods NPR2 was 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. Result Three patients received rhGH therapy for two years, and two NPR2 heterozygous 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. Conclusion In this report, two novel variants in NPR2 gene were described. Our findings broaden the genotypic spectrum of NPR2 variants in individuals with short stature and provid insights into the efficacy of rhGH in these patients. |
| first_indexed | 2024-03-12T21:06:45Z |
| format | Article |
| id | doaj.art-33a852a5a6db46ac8de1ade63eba0085 |
| institution | Directory Open Access Journal |
| issn | 1750-1172 |
| language | English |
| last_indexed | 2024-03-12T21:06:45Z |
| publishDate | 2023-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Orphanet Journal of Rare Diseases |
| spelling | doaj.art-33a852a5a6db46ac8de1ade63eba00852023-07-30T11:24:34ZengBMCOrphanet Journal of Rare Diseases1750-11722023-07-0118111410.1186/s13023-023-02757-8Novel pathogenic NPR2 variants in short stature patients and the therapeutic response to rhGHHong Chen0Suping Zhang1Yunteng Sun2Jiao Chen3Ke Yuan4Ying Zhang5Xiaohong Yang6Xiangquan Lin7Ruimin Chen8Endocrinology Department, Fuzhou Children’s Hospital of Fujian Medical UniversityEndocrinology Department, Fuzhou Children’s Hospital of Fujian Medical UniversityEndocrinology Department, Fuzhou Children’s Hospital of Fujian Medical UniversityDepartment of Pediatrics, The Lin’an People’s HospitalDepartment of Pediatrics, The First Affiliated Hospital of Zhejiang University School of MedicineEndocrinology Department, Fuzhou Children’s Hospital of Fujian Medical UniversityEndocrinology Department, Fuzhou Children’s Hospital of Fujian Medical UniversityEndocrinology Department, Fuzhou Children’s Hospital of Fujian Medical UniversityEndocrinology Department, Fuzhou Children’s Hospital of Fujian Medical UniversityAbstract Objective Heterozygous loss-of-function variants in the NPR2 gene 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 the NPR2 gene and explore the therapeutic response to recombinant growth hormone (rhGH). Methods NPR2 was 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. Result Three patients received rhGH therapy for two years, and two NPR2 heterozygous 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. Conclusion In this report, two novel variants in NPR2 gene were described. Our findings broaden the genotypic spectrum of NPR2 variants in individuals with short stature and provid insights into the efficacy of rhGH in these patients.https://doi.org/10.1186/s13023-023-02757-8NPR2 variantsShort statureLoss-of-function variantsrhGH treatment |
| spellingShingle | Hong Chen Suping Zhang Yunteng Sun Jiao Chen Ke Yuan Ying Zhang Xiaohong Yang Xiangquan Lin Ruimin Chen Novel pathogenic NPR2 variants in short stature patients and the therapeutic response to rhGH Orphanet Journal of Rare Diseases NPR2 variants Short stature Loss-of-function variants rhGH treatment |
| title | Novel pathogenic NPR2 variants in short stature patients and the therapeutic response to rhGH |
| title_full | Novel pathogenic NPR2 variants in short stature patients and the therapeutic response to rhGH |
| title_fullStr | Novel pathogenic NPR2 variants in short stature patients and the therapeutic response to rhGH |
| title_full_unstemmed | Novel pathogenic NPR2 variants in short stature patients and the therapeutic response to rhGH |
| title_short | Novel pathogenic NPR2 variants in short stature patients and the therapeutic response to rhGH |
| title_sort | novel pathogenic npr2 variants in short stature patients and the therapeutic response to rhgh |
| topic | NPR2 variants Short stature Loss-of-function variants rhGH treatment |
| url | https://doi.org/10.1186/s13023-023-02757-8 |
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