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

Christopher T. Esapa, Sian E. Piret, M. Andrew Nesbit, Nellie Y. Loh, Gethin Thomas, Peter I. Croucher, Matthew A. Brown, Steve D. M. Brown, Roger D. Cox, Rajesh V. Thakker

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Abstract

Non-syndromic kyphosis is a common disorder that is associated with significant morbidityand 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 modesof inheritance. To overcome these limitations, we investigated 12 week old progeny of micetreated with the chemical mutagen N-ethyl-N-nitrosourea (ENU) using phenotypic assessmentsincluding dysmorphology, radiography, and dual-energy X-ray absorptiometry. Thisidentified a mouse with autosomal recessive kyphosis (KYLB). KYLB mice, when comparedto unaffected littermates, had: thoraco-lumbar kyphosis, larger vertebrae, and increasedbody length and increased bone area. In addition, female KYLB mice had increases in bonemineral content and plasma alkaline phosphatase activity. Recombination mapping localizedthe 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 Npr3identified a missense mutation, Tyr209Asn, which introduced an N-linked glycosylation consensus sequence. Expression of wild-type NPR3 and the KYLB-associated Tyr209AsnNPR3 mutant in COS-7 cells demonstrated the mutant to be associated with abnormal Nlinkedglycosylation and retention in the endoplasmic reticulum that resulted in its absencefrom 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. Histomorphometricanalysis of KYLB vertebrae and tibiae showed delayed endochondral ossification
Original languageEnglish
Pages (from-to)e0167916
JournalPLoS ONE
Volume11
Issue number12
DOIs
Publication statusPublished - 13 Dec 2016

Keywords

  • kyphosis
  • mutation
  • mouse model
  • signalling

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