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Prevention of guanylyl cyclase–B dephosphorylation rescues achondroplastic dwarfism
Brandon M. Wagner, … , Laurence Legeai-Mallet, Lincoln R. Potter
Brandon M. Wagner, … , Laurence Legeai-Mallet, Lincoln R. Potter
Published March 30, 2021
Citation Information: JCI Insight. 2021;6(9):e147832. https://doi.org/10.1172/jci.insight.147832.
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Research Article Bone biology

Prevention of guanylyl cyclase–B dephosphorylation rescues achondroplastic dwarfism

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Abstract

Activating mutations in the fibroblast growth factor receptor 3 (FGFR3) or inactivating mutations in guanylyl cyclase–B (GC-B), also known as NPR-B or Npr2, cause short-limbed dwarfism. FGFR3 activation causes dephosphorylation and inactivation of GC-B, but the contribution of GC-B dephosphorylation to achondroplasia (ACH) is unknown. GC-B7E/7E mice that express a glutamate-substituted version of GC-B that cannot be inactivated by dephosphorylation were bred with mice expressing FGFR3-G380R, the most common human ACH mutation, to determine if GC-B dephosphorylation is required for ACH. Crossing GC-B7E/7E mice with FGFR3G380R/G380R mice increased naso-anal and long (tibia and femur), but not cranial, bone length twice as much as crossing GC-B7E/7E mice with FGFR3WT/WT mice from 4 to 16 weeks of age. Consistent with increased GC-B activity rescuing ACH, long bones from the GC-B7E/7E/FGFR3G380R/G380R mice were not shorter than those from GC-BWT/WT/FGFR3WT/WT mice. At 2 weeks of age, male but not female FGFR3G380R/G380R mice had shorter long bones and smaller growth plate hypertrophic zones, whereas female but not male GC-B7E/7E mice had longer bones and larger hypertrophic zones. In 2-week-old males, crossing FGFR3G380R/G380R mice with GC-B7E/7E mice increased long bone length and hypertrophic zone area to levels observed in mice expressing WT versions of both receptors. We conclude that preventing GC-B dephosphorylation rescues reduced axial and appendicular skeleton growth in a mouse model of achondroplasia.

Authors

Brandon M. Wagner, Jerid W. Robinson, Yun-Wen Lin, Yi-Ching Lee, Nabil Kaci, Laurence Legeai-Mallet, Lincoln R. Potter

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Figure 1

Expression of 2 GC-B7E/7E alleles rescues the naso-anal length but not the midface hypoplasia defect in FGFR3G380R/G380R mice.

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Expression of 2 GC-B7E/7E alleles rescues the naso-anal length but not t...
Male 16-week-old mice of the indicated genotype are shown for visual comparison. The WT or mutant versions of the FGFR3 or GC-B genes that are expressed in each line are shown at the bottom of the figure. The red arrows indicate midface hypoplasia.

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