Mutation analysis in Costello syndrome: Functional and structural characterization of the HRAS p.Lys 117Arg mutation
Mutation analysis in Costello syndrome: Functional and structural characterization of the HRAS p.Lys 117Arg mutation
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DOI：
10.1002/humu.20616
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发表时间：
2008-02-01
期刊：
影响因子：
3.9
通讯作者：
Legius, Eric
中科院分区：
文献类型：
--
作者：
Denayer, Ellen;Parret, Annabel;Legius, Eric
科斯特洛综合征是一种智力低下综合征，其特点是出生体重高、出生后生长迟缓、面部粗糙、皮肤松弛、心血管问题和肿瘤易感性。HRAS密码子12和13的新杂合错义突变干扰了内在的GTP水解，导致Costello综合征。我们报告一个病人。典型的Costello综合征和HRAS基因密码子117 （c.350A > G, p.Lys 117Arg）的新杂合错义突变，导致RAS/MAPK通路的组成性激活，类似于典型的p.g yl2ser和p.g yl2ala突变。重组HRAS p.Lys117Arg表现出正常的GTP水解和对GTP酶激活蛋白的响应性，但核苷酸解离率提高了80倍。与生化数据一致，p.Lys 117Arg突变体的晶体结构表明侧链的相互作用模式发生了改变，这与不利的核苷酸结合特性有关。总之，这些数据表明，仅干扰鸟嘌呤核苷酸结合的RAS突变与损害GTP水解并导致人类疾病的突变具有相似的功能后果。
Costello syndrome is a mental retardation syndrome characterized by high birth weight, postnatal growth retardation, coarse face, loose skin, cardiovascular problems, and tumor predisposition. De novo heterozygous missense mutations in HRAS codon 12 and 13 disturbing the intrinsic GTP hydrolysis cause Costello syndrome. We report a patient with. typical Costello syndrome and a novel heterozygous missense mutation in codon 117 (c.350A > G, p.Lys 117Arg) of the HRAS gene, resulting in constitutive activation of the RAS/MAPK pathway similar to the typical p.Glyl2Ser and p.Glyl2Ala mutations. Recombinant HRAS p.Lys117Arg demonstrates normal intrinsic GTP hydrolysis and responsiveness to GTPase-activating proteins, but the nucleotide dissociation rate is increased 80-fold. Consistent with the biochemical data, the crystal structure of the p.Lys 117Arg mutant indicates an altered interaction pattern of the side chain that is associated with unfavorable nucleotide binding properties. Together, these data show that a RAS mutation that only perturbs guanine nucleotide binding has similar functional consequences as mutations that impair GTP hydrolysis and causes human disease.