Tavormina P L, Bellus G A, Webster M K, Bamshad M J, Fraley A E, McIntosh I, Szabo J, Jiang W, Jabs E W, Wilcox W R, Wasmuth J J, Donoghue D J, Thompson L M, Francomano C A
Department of Biological Chemistry, University of California, Irvine, CA, USA.
Am J Hum Genet. 1999 Mar;64(3):722-31. doi: 10.1086/302275.
We have identified a novel fibroblast growth factor receptor 3 (FGFR3) missense mutation in four unrelated individuals with skeletal dysplasia that approaches the severity observed in thanatophoric dysplasia type I (TD1). However, three of the four individuals developed extensive areas of acanthosis nigricans beginning in early childhood, suffer from severe neurological impairments, and have survived past infancy without prolonged life-support measures. The FGFR3 mutation (A1949T: Lys650Met) occurs at the nucleotide adjacent to the TD type II (TD2) mutation (A1948G: Lys650Glu) and results in a different amino acid substitution at a highly conserved codon in the kinase domain activation loop. Transient transfection studies with FGFR3 mutant constructs show that the Lys650Met mutation causes a dramatic increase in constitutive receptor kinase activity, approximately three times greater than that observed with the Lys650Glu mutation. We refer to the phenotype caused by the Lys650Met mutation as "severe achondroplasia with developmental delay and acanthosis nigricans" (SADDAN) because it differs significantly from the phenotypes of other known FGFR3 mutations.
我们在四名患骨骼发育不良的非亲缘个体中鉴定出一种新的成纤维细胞生长因子受体3（FGFR3）错义突变，其严重程度接近I型致死性发育不良（TD1）中观察到的情况。然而，这四名个体中的三名在幼儿期开始出现广泛的黑棘皮病区域，患有严重的神经功能障碍，并且在没有长期生命维持措施的情况下存活至婴儿期之后。FGFR3突变（A1949T：赖氨酸650突变为甲硫氨酸）发生在与II型TD（TD2）突变（A1948G：赖氨酸650突变为谷氨酸）相邻的核苷酸处，并导致激酶结构域激活环中一个高度保守密码子处发生不同的氨基酸替换。对FGFR3突变体构建体进行的瞬时转染研究表明，赖氨酸650突变为甲硫氨酸的突变导致组成型受体激酶活性显著增加，大约是赖氨酸650突变为谷氨酸的突变所观察到的活性的三倍。我们将赖氨酸650突变为甲硫氨酸的突变所导致的表型称为“伴有发育迟缓与黑棘皮病的严重软骨发育不全”（SADDAN），因为它与其他已知FGFR3突变的表型有显著差异。
