Highly activated Fgfr3 with the K644M mutation causes prolonged survival in severe dwarf mice
Highly activated Fgfr3 with the K644M mutation causes prolonged survival in severe dwarf mice
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DOI：
10.1093/hmg/10.12.1255
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发表时间：
2001-06-01
影响因子：
3.5
通讯作者：
Francomano, CA
中科院分区：
文献类型：
--
作者：
Iwata, T;Li, CL;Francomano, CA
受体酪氨酸激酶成纤维细胞生长因子受体3（FGFR3）中的几种功能获得性突变导致人类侏儒症。两种特别严重的侏儒症，致死性发育不良II型（TDII）和严重软骨发育不全伴发育迟缓和黑棘皮病（SADDAN），与激酶结构域中K650残基的谷氨酸（E）和甲硫氨酸（M）取代有关。TDII在出生时是致命的，而大多数SADDAN患者在围产期存活。然而，在体外，具有SADDAN突变的FGFR 3比具有TDII突变的FGFR 3更活化。为了找出K650M突变是否也导致SADDAN表型，我们将相应的点突变（K644M）引入小鼠Fgfr 3基因。杂合突变小鼠表现出与人SADDAN相似的表型，例如，大多数SADDAN小鼠在围产期存活。这表明SADDAN患者的存活确实归因于FGFR3中的K650M突变。SADDAN小鼠中的长骨异常比TDII模型轻。此外，在肋软骨、气管和鼻中隔中观察到软骨组织的过度生长。低浓度的FGF配体在来自野生型和SADDAN小鼠的原代软骨细胞培养物中差异地激活Map激酶，比较SADDAN和TDII小鼠表型差异的分子基础，可能会增加我们对影响这两种相关骨骼发育不良严重程度的因素的理解。
Several gain-of-function mutations in a receptor tyrosine kinase, fibroblast growth factor receptor 3 (FGFR3), cause dwarfism in humans. Two particularly severe dwarfisms, thanatophoric dysplasia type II (TDII) and severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), are associated with glutamic acid (E) and methionine (M) substitutions at the K650 residue in the kinase domain, TDII is lethal at birth, whereas most of the SADDAN patients survive the perinatal period. However, FGFR3 with the SADDAN mutation is more activated than FGFR3 with the TDII mutation in vitro. To find out whether the K650M mutation also causes the SADDAN phenotype, we introduced the corresponding point mutation (K644M) into the mouse Fgfr3 gene. Heterozygous mutant mice show a phenotype similar to human SADDAN, e,g, the majority of the SADDAN mice survive the perinatal period. This suggests that the survival of SADDAN patients is indeed attributed to the K650M mutation in FGFR3, The long bone abnormalities in SADDAN mice are milder than the TDII model, In addition, overgrowth of the cartilaginous tissues is observed in the rib cartilage, trachea and nasal septum, The FGF ligand at the low concentration differentially activates Map kinase in primary chondrocyte cultures from wildtype and SADDAN mice, Comparisons of the molecular bases of the phenotypic differences in SADDAN and TDII mice may increase our understanding of the factors that influence the severity in these two related skeletal dysplasias.