Toydemir Reha M, Brassington Anna E, Bayrak-Toydemir Pinar, Krakowiak Patrycja A, Jorde Lynn B, Whitby Frank G, Longo Nicola, Viskochil David H, Carey John C, Bamshad Michael J
Department of Human Genetics, University of Utah, Salt Lake City, UT, USA.
Am J Hum Genet. 2006 Nov;79(5):935-41. doi: 10.1086/508433. Epub 2006 Sep 26.
Activating mutations of FGFR3, a negative regulator of bone growth, are well known to cause a variety of short-limbed bone dysplasias and craniosynostosis syndromes. We mapped the locus causing a novel disorder characterized by camptodactyly, tall stature, scoliosis, and hearing loss (CATSHL syndrome) to chromosome 4p. Because this syndrome recapitulated the phenotype of the Fgfr3 knockout mouse, we screened FGFR3 and subsequently identified a heterozygous missense mutation that is predicted to cause a p.R621H substitution in the tyrosine kinase domain and partial loss of FGFR3 function. These findings indicate that abnormal FGFR3 signaling can cause human anomalies by promoting as well as inhibiting endochondral bone growth.
FGFR3是骨生长的负调节因子，其激活突变众所周知会导致多种短肢骨发育不良和颅缝早闭综合征。我们将导致一种以屈曲指、身材高大、脊柱侧弯和听力丧失为特征的新型疾病（CATSHL综合征）的基因座定位到了4号染色体短臂。由于该综合征重现了Fgfr3基因敲除小鼠的表型，我们对FGFR3进行了筛查，随后鉴定出一个杂合错义突变，预计该突变会导致酪氨酸激酶结构域中的p.R621H替代以及FGFR3功能部分丧失。这些发现表明，异常的FGFR3信号传导可通过促进和抑制软骨内骨生长导致人类异常。
