Physical basis behind achondroplasia, the most common form of human dwarfism.

The Journal of Biological Chemistry
Lijuan HeKalina Hristova

Abstract

Fibroblast growth factor receptor 3 (FGFR3) is a receptor tyrosine kinase that plays an important role in long bone development. The G380R mutation in FGFR3 transmembrane domain is known as the genetic cause for achondroplasia, the most common form of human dwarfism. Despite many studies, there is no consensus about the exact mechanism underlying the pathology. To gain further understanding into the physical basis behind the disorder, here we measure the activation of wild-type and mutant FGFR3 in mammalian cells using Western blots, and we analyze the activation within the frame of a physical-chemical model describing dimerization, ligand binding, and phosphorylation probabilities within the dimers. The data analysis presented here suggests that the mutation does not increase FGFR3 dimerization, as proposed previously. Instead, FGFR3 activity in achondroplasia is increased due to increased probability for phosphorylation of the unliganded mutant dimers. This finding has implications for the design of targeted molecular treatments for achondroplasia.

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Citations

Sep 8, 2011·Biochemistry·Fenghao Chen, Kalina Hristova
Feb 18, 2011·The Journal of Biological Chemistry·Lijuan HeKalina Hristova
Jun 7, 2013·Human Molecular Genetics·Deepali N ShindeIrene Tiemann-Boege
Jan 5, 2016·Nature Communications·Sarvenaz Sarabipour, Kalina Hristova
Aug 21, 2013·American Journal of Medical Genetics. Part a·Beáta BessenyeiEva Oláh
May 7, 2021·Science Translational Medicine·Takeshi KimuraPavel Krejci
Aug 8, 2021·Orphanet Journal of Rare Diseases·Kathryn M PfeifferR Will Charlton
Dec 28, 2018·Chemical Reviews·Michael D Paul, Kalina Hristova
Aug 26, 2021·Global Medical Genetics·Mahmut C ErgorenSehime Gulsun Temel
Oct 14, 2021·American Journal of Medical Genetics. Part a·Kathryn M PfeifferR Will Charlton
Jul 20, 2011·Journal of Molecular Biology·Lijuan HeWilliam C Wimley
Aug 16, 2011·Biochimica Et Biophysica Acta·Lijuan He, Kalina Hristova

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