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Novel NPR2 Gene Mutations Affect Chondrocytes Function via ER Stress in Short Stature

Natriuretic peptide receptor 2 (NPR2) plays a key role in cartilage and bone morphogenesis. The NPR2 gene mutations result in acromesomelic dysplasia, Maroteaux type (AMDM), short stature with nonspecific skeletal abnormalities (SNSK), and epiphyseal chondrodysplasia, Miura type (ECDM). However, the...

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Autores principales: Li, Qiuyue, Fan, Xin, Lu, Wei, Sun, Chengjun, Pei, Zhou, Zhang, Miaoying, Ni, Jinwen, Wu, Jing, Yu, Fa-Xing, Luo, Feihong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9024524/
https://www.ncbi.nlm.nih.gov/pubmed/35455946
http://dx.doi.org/10.3390/cells11081265
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author Li, Qiuyue
Fan, Xin
Lu, Wei
Sun, Chengjun
Pei, Zhou
Zhang, Miaoying
Ni, Jinwen
Wu, Jing
Yu, Fa-Xing
Luo, Feihong
author_facet Li, Qiuyue
Fan, Xin
Lu, Wei
Sun, Chengjun
Pei, Zhou
Zhang, Miaoying
Ni, Jinwen
Wu, Jing
Yu, Fa-Xing
Luo, Feihong
author_sort Li, Qiuyue
collection PubMed
description Natriuretic peptide receptor 2 (NPR2) plays a key role in cartilage and bone morphogenesis. The NPR2 gene mutations result in acromesomelic dysplasia, Maroteaux type (AMDM), short stature with nonspecific skeletal abnormalities (SNSK), and epiphyseal chondrodysplasia, Miura type (ECDM). However, the pathogenic mechanism remains unclear. In our study, we identified one de novo (R557C) and six novel variants (G602W, V970F, R767*, R363*, F857S, and Y306S) in five independent Chinese families with familial short stature. Three patients with heterozygous mutations (G602W, V970F, and R767*) were diagnosed with SNSK (height SD score ranged from −2.25 to −5.60), while another two with compound heterozygous mutations (R363* and F857S, R557C and Y306S) were diagnosed with AMDM (height SD score ranged from −3.10 to −5.35). Among three patients with heterozygous status, two patients before puberty initiation with rhGH treatment significantly improved their growth (height velocity 7.2 cm/year, 6.0 cm/year), and one patient in puberty had a poor response to the rhGH treatment (height velocity 2.5 cm/year). Seven NPR2 gene variants were constructed and overexpressed in HEK293T and ATDC5 cells, and we found that ATDC5 cells with mutant NPR2 gene showed decreased differentiation, as evidenced by lower expression of ColII, ColX, and BMP4 and higher expression of Sox9. Moreover, the apoptosis rate was elevated in ATDC5 cells expressing the mutant NPR2 gene. N-glycosylation modification, plasma membrane localization, and ER stress resulted from the accumulation of mutant protein in ER, as shown by the higher expression of GRP78 and p-IRE1α. Overall, our results provide a novel insight into NPR2 loss of function, which could promote chondrocyte apoptosis and repress cell differentiation through ER stress and the unfolded protein response.
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spelling pubmed-90245242022-04-23 Novel NPR2 Gene Mutations Affect Chondrocytes Function via ER Stress in Short Stature Li, Qiuyue Fan, Xin Lu, Wei Sun, Chengjun Pei, Zhou Zhang, Miaoying Ni, Jinwen Wu, Jing Yu, Fa-Xing Luo, Feihong Cells Article Natriuretic peptide receptor 2 (NPR2) plays a key role in cartilage and bone morphogenesis. The NPR2 gene mutations result in acromesomelic dysplasia, Maroteaux type (AMDM), short stature with nonspecific skeletal abnormalities (SNSK), and epiphyseal chondrodysplasia, Miura type (ECDM). However, the pathogenic mechanism remains unclear. In our study, we identified one de novo (R557C) and six novel variants (G602W, V970F, R767*, R363*, F857S, and Y306S) in five independent Chinese families with familial short stature. Three patients with heterozygous mutations (G602W, V970F, and R767*) were diagnosed with SNSK (height SD score ranged from −2.25 to −5.60), while another two with compound heterozygous mutations (R363* and F857S, R557C and Y306S) were diagnosed with AMDM (height SD score ranged from −3.10 to −5.35). Among three patients with heterozygous status, two patients before puberty initiation with rhGH treatment significantly improved their growth (height velocity 7.2 cm/year, 6.0 cm/year), and one patient in puberty had a poor response to the rhGH treatment (height velocity 2.5 cm/year). Seven NPR2 gene variants were constructed and overexpressed in HEK293T and ATDC5 cells, and we found that ATDC5 cells with mutant NPR2 gene showed decreased differentiation, as evidenced by lower expression of ColII, ColX, and BMP4 and higher expression of Sox9. Moreover, the apoptosis rate was elevated in ATDC5 cells expressing the mutant NPR2 gene. N-glycosylation modification, plasma membrane localization, and ER stress resulted from the accumulation of mutant protein in ER, as shown by the higher expression of GRP78 and p-IRE1α. Overall, our results provide a novel insight into NPR2 loss of function, which could promote chondrocyte apoptosis and repress cell differentiation through ER stress and the unfolded protein response. MDPI 2022-04-08 /pmc/articles/PMC9024524/ /pubmed/35455946 http://dx.doi.org/10.3390/cells11081265 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Li, Qiuyue
Fan, Xin
Lu, Wei
Sun, Chengjun
Pei, Zhou
Zhang, Miaoying
Ni, Jinwen
Wu, Jing
Yu, Fa-Xing
Luo, Feihong
Novel NPR2 Gene Mutations Affect Chondrocytes Function via ER Stress in Short Stature
title Novel NPR2 Gene Mutations Affect Chondrocytes Function via ER Stress in Short Stature
title_full Novel NPR2 Gene Mutations Affect Chondrocytes Function via ER Stress in Short Stature
title_fullStr Novel NPR2 Gene Mutations Affect Chondrocytes Function via ER Stress in Short Stature
title_full_unstemmed Novel NPR2 Gene Mutations Affect Chondrocytes Function via ER Stress in Short Stature
title_short Novel NPR2 Gene Mutations Affect Chondrocytes Function via ER Stress in Short Stature
title_sort novel npr2 gene mutations affect chondrocytes function via er stress in short stature
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9024524/
https://www.ncbi.nlm.nih.gov/pubmed/35455946
http://dx.doi.org/10.3390/cells11081265
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