Distinct missense mutations of the FCFR3 Lys650 codon modulate receptor kinase activation and the severity of the skeletal dysplasia phenotype
Distinct missense mutations of the FCFR3 Lys650 codon modulate receptor kinase activation and the severity of the skeletal dysplasia phenotype
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DOI：
10.1086/316892
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发表时间：
2000-12-01
影响因子：
9.8
通讯作者：
Francomano, CA
中科院分区：
文献类型：
--
作者：
Bellus, GA;Spector, EB;Francomano, CA
成纤维细胞生长因子受体3（FGFR3）LYS650密码子位于酪氨酸激酶 - 域激活环的关键区域内，已知该密码子中的两个错义突变可导致FGFR3酪氨酸激酶的强大组成型激活，并导致三种不同骨骼发育不良综合征 - 跨性增生II型（TD2） （A1948G [LYS650GLU]）和SADDAN（严重的延迟延迟和棘皮动物鼻孔）综合征和I型I型（TD1）（均由A1949T [lys650met]）。已知FGFR3酪氨酸激酶结构域内的其他突变（例如C1620A或C1620G [均导致ASN540LYS]）引起下降体内质质症，一种相对常见但相对较轻但较温和的骨骼倍增倍障碍。在没有ASN540LYS突变的90名怀疑临床诊断的临床诊断的人中，我们在FGFR3外显子15中筛选了突变，该突变会破坏包括Lys650密码子在内的独特的BBSI限制性位点。我们在这里报告了来自五个家庭的六个人，发现了三个新型突变（G1950T和G1950C [均导致Lys650ASN]和A1948C [LYS650GLN]）。这些个体的几个物理和放射学特征比患有ASN540LYS突变的个体的人明显温和。 LYS650ASN/GLN突变导致FGFR3酪氨酸激酶的组成型激活，但程度较小，而Lys540GLU和Lys650met突变的程度较小。这些结果表明，FGFR3 LYS650密码子处的不同氨基酸取代可以导致几种不同的骨骼发育异常表型。
The fibroblast growth factor-receptor 3 (FGFR3) Lys650 codon is located within a critical region of the tyrosine kinase-domain activation loop, Two missense mutations in this codon are known to result in strong constitutive activation of the FGFR3 tyrosine kinase and cause three different skeletal dysplasia syndromes-thanatophoric dysplasia type II (TD2) (A1948G [Lys650Glu]) and SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans) syndrome and thanatophoric dysplasia type I (TD1) (both due to A1949T [Lys650Met]). Other mutations within the FGFR3 tyrosine kinase domain (e.g., C1620A or C1620G [both resulting in Asn540Lys]) are known to cause hypochondroplasia, a relatively common but milder skeletal dysplasia. In 90 individuals with suspected clinical diagnoses of hypochondroplasia who do not have Asn540Lys mutations, we screened for mutations, in FGFR3 exon 15, that would disrupt a unique BbsI restriction site that includes the Lys650 codon. We report here the discovery of three novel mutations (G1950T and G1950C [both resulting in Lys650Asn] and A1948C [Lys650Gln]) occurring in six individuals from five families. Several physical and radiological features of these individuals were significantly milder than those in individuals with the Asn540Lys mutations. The Lys650Asn/Gln mutations result in constitutive activation of the FGFR3 tyrosine kinase but to a lesser degree than that observed with the Lys540Glu and Lys650Met mutations. These results demonstrate that different amino acid substitutions at the FGFR3 Lys650 codon can result in several different skeletal dysplasia phenotypes.