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Nature Medicine:KINDLIN3基因点突变涉及整合素活性改变

来源:医学空间 2009-03-09 12:42

《自然医学》杂志报道,美国科研人员通过2例特殊遗传病发现KINDLIN3基因点突变影响整合素活性。

2例同胞患者,幼年出现严重出血、反复感染和骨硬化症状,这与白细胞粘附缺陷III  (LAD-III)症状类似,但情况更为严重。这些症状是由于造血细胞无法表达活性整合素所至。从2例患者分离得到的永生化白细胞株显示整合素激活缺陷。整合素激活与多种蛋白质有关,其中包括Ras相关蛋白1  (RAP1)、钙及CALDAG-GEF1。这种疾病存在KINDLIN3基因编码区点突变  (官方基因编码称FERMT3  )。

由此可见,KINDLIN3在人体整合素激活中有重要作用。此外,异基因骨髓移植可以缓解症状。(生物谷Bioon.com)

生物谷推荐原始出处:

Nature Medicine 15, 306 - 312 (2009) 22 February 2009 | doi:10.1038/nm.1931

Leukocyte adhesion deficiency-III is caused by mutations in KINDLIN3 affecting integrin activation

Lena Svensson1,6, Kimberley Howarth2,6, Alison McDowall1, Irene Patzak1, Rachel Evans1, Siegfried Ussar3, Markus Moser3, Ayse Metin4, Mike Fried5, Ian Tomlinson2 & Nancy Hogg1

Integrins are the major adhesion receptors of leukocytes and platelets. 1 and 2 integrin function on leukocytes is crucial for a successful immune response and the platelet integrin IIb3 initiates the process of blood clotting through binding fibrinogen1, 2, 3. Integrins on circulating cells bind poorly to their ligands but become active after 'inside-out' signaling through other membrane receptors4, 5. Subjects with leukocyte adhesion deficiency-1 (LAD-I) do not express 2 integrins because of mutations in the gene specifying the 2 subunit, and they suffer recurrent bacterial infections6, 7. Mutations affecting IIb3 integrin cause the bleeding disorder termed Glanzmann's thrombasthenia3. Subjects with LAD-III show symptoms of both LAD-I and Glanzmann's thrombasthenia. Their hematopoietically-derived cells express 1, 2 and 3 integrins, but defective inside-out signaling causes immune deficiency and bleeding problems8. The LAD-III lesion has been attributed to a C  A mutation in the gene encoding calcium and diacylglycerol guanine nucleotide exchange factor (CALDAGGEF1; official symbol RASGRP2) specifying the CALDAG-GEF1 protein9, but we show that this change is not responsible for the LAD-III disorder. Instead, we identify mutations in the KINDLIN3 (official symbol FERMT3) gene specifying the KINDLIN-3 protein as the cause of LAD-III in Maltese and Turkish subjects. Two independent mutations result in decreased KINDLIN3 messenger RNA levels and loss of protein expression. Notably, transfection of the subjects' lymphocytes with KINDLIN3 complementary DNA but not CALDAGGEF1 cDNA reverses the LAD-III defect, restoring integrin-mediated adhesion and migration.

1 Leukocyte Adhesion Laboratory, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
2 Molecular and Population Genetics Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
3 Department of Molecular Medicine, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
4 Division of Immunology, SB Ankara Diskapi Children's Hospital, 06110 Ankara, Turkey.
5 University of California–San Francisco Cancer Research Institute, 2340 Sutter Street, San Francisco, California 94115, USA.
6 These authors contributed equally to this work.

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