Functional, Structural, and Genetic Evaluation of 20 CDKN2A Germ Line Mutations Identified in Melanoma-Prone Families or Patients
Functional, Structural, and Genetic Evaluation of 20 CDKN2A Germ Line Mutations Identified in Melanoma-Prone Families or Patients
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DOI：
10.1002/humu.20845
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发表时间：
2009-04-01
期刊：
影响因子：
3.9
通讯作者：
Bressac-de Paillerets, Brigitte
中科院分区：
文献类型：
--
作者：
Kannengiesser, Caroline;Brookes, Sharon;Bressac-de Paillerets, Brigitte
CDKN 2A基因的生殖系突变见于黑色素瘤易感家族和患有多发性散发性黑色素瘤的个体。编码的蛋白质p16（INK 4A）包含四个锚定型重复序列，并且突变（其中大部分是错义的并且发生在整个编码区中）破坏这些结构基序的构象以及p16（INK 4a）与其生理靶点（细胞周期蛋白依赖性激酶（CDK）CDK 4和CDK 6）的关联。评估非同义突变的致病性对于评估携带者的黑色素瘤风险至关重要。在本研究中，我们研究了20个CDKN 2A种系突变对p16 INK 4A结构和功能的影响，这些在以前没有记录。（Thr18_Ala19dup，Gly23Asp，Arg24Gln，Gly35Ala，Gly35Val，Ala57Val，Ala60Val，Ala60Arg，Leu65dup，Gly67Arg，Gly67_Asn71del，Glu69Gly，Asp74Tyr，Thr77Pro，Arg80Pro，Pro81Thr，Arg87Trp，Leu97Arg、Arg99Pro和[Leu113Leu;Pro114Ser]）。通过考虑遗传信息，每个变体对蛋白质结构的预测影响，其与CDK 4相互作用的能力以及在实验环境中阻碍细胞增殖，我们得出结论，20个CDKN 2A变体中有18个可以归类为Lis功能丧失突变，而两个的结果仍然不明确。区分p16（INK 4A）的突变体和中性变体不仅增加了我们对蛋白质中功能关键残基的理解，而且提供了用于黑色素瘤风险预测的信息。《Mutat》30，564-574，2009年。(C)2009 Wiley-Liss，Inc.
Germline Mutations of the CDKN2A gene are found in melanoma-prone families and individuals with multiple sporadic melanomas. The encoded protein, p16(INK4A), comprises four ankyrin-type repeats, and the mutations, most of which are missense and occur throughout the entire coding region, call disrupt the conformation of these structural motifs as well as the association of p16(INK4a) its physiological targets, the cyclin-dependent kinases (CDKs) CDK4 and CDK6. Assessing pathogenicity of nonsynonymous Mutations is critical to evaluate melanoma risk in carriers. In the current study we investigate 20 CDKN2A germline mutations effects oil p16INK4A structure and function have not been previously documented (Thr18_Ala19dup, Gly23Asp, Arg24Gln, Gly35Ala, Gly35Val, Ala57Val, Ala60Val, Ala60Arg, Leu65dup, Gly67Arg, Gly67_Asn71del, Glu69Gly, Asp74Tyr, Thr77Pro, Arg80Pro, Pro81Thr, Arg87Trp, Leu97Arg, Arg99Pro, and [Leu 113Leu;Pro114Ser]). By considering genetic information, the predicted impact of each variant oil the protein structure, its ability to interact with CDK4 and impede cell proliferation in experimental settings, We conclude that 18 of the 20 CDKN2A variants can be classed Lis loss of function mutations, whereas the results for two remain ambiguous. Discriminating between mutant and neutral variants of p16(INK4A) not only adds to our understanding of the functionally critical residues in the protein but provides information that call be used for melanoma risk prediction. Hum Mutat 30, 564-574, 2009. (C) 2009 Wiley-Liss, Inc.