Mice with an N-Ethyl-N-Nitrosourea (ENU) induced Tyr209Asn mutation in natriuretic peptide receptor 3 (NPR3) provide a model for kyphosis associated with activation of the MAPK signaling pathway

Esapa, Christopher T., Piret, Sian E., Nesbit, M. Andrew, Loh, Nellie Y., Thomas, Gethin, Croucher, Peter I., Brown, Matthew A., Brown, Steve D. M., Cox, Roger D. and Thakker, Rajesh V. (2016) Mice with an N-Ethyl-N-Nitrosourea (ENU) induced Tyr209Asn mutation in natriuretic peptide receptor 3 (NPR3) provide a model for kyphosis associated with activation of the MAPK signaling pathway. Plos One, 11 12: . doi:10.1371/journal.pone.0167916


Author Esapa, Christopher T.
Piret, Sian E.
Nesbit, M. Andrew
Loh, Nellie Y.
Thomas, Gethin
Croucher, Peter I.
Brown, Matthew A.
Brown, Steve D. M.
Cox, Roger D.
Thakker, Rajesh V.
Title Mice with an N-Ethyl-N-Nitrosourea (ENU) induced Tyr209Asn mutation in natriuretic peptide receptor 3 (NPR3) provide a model for kyphosis associated with activation of the MAPK signaling pathway
Formatted title
Mice with an N-Ethyl-N-Nitrosourea (ENU) induced Tyr209Asn mutation in natriuretic peptide receptor 3 (NPR3) provide a model for kyphosis associated with activation of the MAPK signaling pathway
Journal name Plos One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2016-12-13
Year available 2016
Sub-type Article (original research)
DOI 10.1371/journal.pone.0167916
Open Access Status DOI
Volume 11
Issue 12
Total pages 18
Place of publication San Francisco, CA, United States
Publisher Public Library of Science
Collection year 2017
Language eng
Formatted abstract
Non-syndromic kyphosis is a common disorder that is associated with significant morbidity and has a strong genetic involvement; however, the causative genes remain to be identified, as such studies are hampered by genetic heterogeneity, small families and various modes of inheritance. To overcome these limitations, we investigated 12 week old progeny of mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU) using phenotypic assessments including dysmorphology, radiography, and dual-energy X-ray absorptiometry. This identified a mouse with autosomal recessive kyphosis (KYLB). KYLB mice, when compared to unaffected littermates, had: thoraco-lumbar kyphosis, larger vertebrae, and increased body length and increased bone area. In addition, female KYLB mice had increases in bone mineral content and plasma alkaline phosphatase activity. Recombination mapping localized the Kylb locus to a 5.5Mb region on chromosome 15A1, which contained 51 genes, including the natriuretic peptide receptor 3 (Npr3) gene. DNA sequence analysis of Npr3 identified a missense mutation, Tyr209Asn, which introduced an N-linked glycosylation consensus sequence. Expression of wild-type NPR3 and the KYLB-associated Tyr209Asn NPR3 mutant in COS-7 cells demonstrated the mutant to be associated with abnormal N-linked glycosylation and retention in the endoplasmic reticulum that resulted in its absence from the plasma membrane. NPR3 is a decoy receptor for C-type natriuretic peptide (CNP), which also binds to NPR2 and stimulates mitogen-activated protein kinase (MAPK) signaling, thereby increasing the number and size of hypertrophic chondrocytes. Histomorphometric analysis of KYLB vertebrae and tibiae showed delayed endochondral ossification and expansion of the hypertrophic zones of the growth plates, and immunohistochemistry revealed increased p38 MAPK phosphorylation throughout the growth plates of KYLB vertebrae. Thus, we established a model of kyphosis due to a novel NPR3 mutation, in which loss of plasma membrane NPR3 expression results in increased MAPK pathway activation, causing elongation of the vertebrae and resulting in kyphosis.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
UQ Diamantina Institute Publications
 
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