Molecular diversity of Glanzmann thrombasthenia in southern India:: New insights into mRNA splicing and structure-function correlations of αIIbβ3 integrin (ITGA2B, ITGB3)
Molecular diversity of Glanzmann thrombasthenia in southern India:: New insights into mRNA splicing and structure-function correlations of αIIbβ3 integrin (ITGA2B, ITGB3)
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DOI：
10.1002/humu.20304
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发表时间：
2006-04-01
期刊：
影响因子：
3.9
通讯作者：
Seligsohn, U
中科院分区：
文献类型：
--
作者：
Peretz, H;Rosenberg, N;Seligsohn, U
在印度南部的 40 个家族中研究了格兰兹曼血栓形成 (GT) 的分子基础。在 23 个已识别的突变中（13 个位于 alpha IIb (ITGA2B) 基因，10 个位于 beta 3 (ITGB3) 基因），其中 20 个是新突变，其中 3 个是之前描述过的。分别在 12 个、3 个和 2 个家族中检测到了 beta 3 基因的三个突变 - p.Leu143Trp (Leu117Trp)、p.Tyr307Stop (Tyr281Stop) 和 p.Arg119GIn (Arg93GIn)，并且在前两个突变中观察到了明确的创始人效应。在计算机上预测了 β 3 基因的正常变体和错义变体，以及 α IIb 或 β 3 中的 10/11 移码或无义突变的选择性剪接。该预测通过实验证实了 α IIb 基因外显子 28 中的 c.2898_2902dupCCCCT 突变（诱导外显子跳跃）。九个错义突变中的七个取代了埋藏在蛋白质核心中的高度保守的氨基酸，预测结构异常。其中，03 取代 p.Cys39Gly (Cys13Gly) 被发现会导致 β 3 亚基的细胞内降解，与之前的研究结果相反，二硫键中 Cys13 的伙伴 Cys435 的突变会导致 α IIb β 3 的组成型激活。两名具有 β 3 Arg93GIn 突变的患者具有正常的血栓回缩，与 最近发现，这种取代与 α IIb beta 3 的正常表面表达有关。总之，这项研究表明，印度南部患者的 GT 存在多种突变，为 mRNA 剪接提供了新的见解，并强调了特定氨基酸在 α IIb beta 3 结构功能相关性中的作用。
The molecular basis of Glanzmann thrombastlienia (GT) was studied in 40 families from southern India. Of 23 identified mutations (13 in the alpha IIb (ITGA2B) gene and 10 in the beta 3 (ITGB3) gene), 20 were novel and three were described previously. Three mutations in the beta 3 gene-p.Leu143Trp (Leu117Trp), p.Tyr307Stop (Tyr281Stop), and p.Arg119GIn (Arg93GIn)-were detected in 12, three, and two families, respectively, with definite founder effects observed for the first two mutations. Alternative splicing was predicted in silico for the normal variant and a missense variant of the beta 3 gene, and for 10/11 frameshift or nonsense mutations in alpha IIb or beta 3. The prediction was confirmed experimentally for a c.2898_2902dupCCCCT Mutation in exon 28 of the alpha IIb gene that induced exon skipping. Seven Out of nine missense mutations substituted highly conserved amino acids buried in the proteins' cores, predicting structural abnormalities. Among these, a 03 substitution, p.Cys39Gly (Cys13GIy) was found to cause intracellular degradation of the beta 3 subunit, in contrast to previous findings that mutations at Cys435, the partner of Cys13 in a disulfide bond, cause constitutive activation of alpha IIb beta 3. The two patients with a beta 3 Arg93GIn mutation had normal clot retraction, consistent with a recent finding that this substitution is associated with normal surface expression of alpha IIb beta 3. In conclusion, this study demonstrates that a variety of mutations account for GT in southern Indian patients, provides new insights into mRNA splicing, and highlights the role of specific amino acids in structure-function correlations of alpha IIb beta 3.