Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, USA.
Department of Pediatrics, University of Wisconsin, Madison, Wisconsin, USA.
Am J Med Genet A. 2021 Mar;185(3):798-805. doi: 10.1002/ajmg.a.62043. Epub 2020 Dec 2.
We describe an individual in whom clinical and radiographic features are typical for achondroplasia, but in whom the common variants of FGFR3 that result in achondroplasia are absent. Whole exome sequencing demonstrated a novel, de novo 6 base pair tandem duplication in FGFR3 that results in the insertion of Ser-Phe after position Leu324. in vitro studies showed that this variant results in aberrant dimerization, excessive spontaneous phosphorylation of FGFR3 dimers and excessive, ligand-independent tyrosine kinase activity. Together, these data suggest that this variant leads to constitutive disulfide bond-mediated dimerization, and that this, surprisingly, occurs to an extent similar to the neonatal lethal thanatophoric dysplasia type I Ser249Cys variant.
我们描述了一名个体，其临床表现和影像学特征均符合软骨发育不全，但不存在导致软骨发育不全的 FGFR3 常见变异。全外显子组测序显示 FGFR3 中存在一个新的、从头产生的 6 碱基对串联重复，导致 Leu324 后插入丝氨酸-苯丙氨酸。体外研究表明，该变体导致异常二聚化、FGFR3 二聚体过度自发磷酸化和过度的、配体非依赖性酪氨酸激酶活性。这些数据表明，该变体导致组成型二硫键介导的二聚化，令人惊讶的是，这种二聚化的程度与导致新生儿致死性Thanatophoric 发育不良 I 型 Ser249Cys 变体的程度相似。
