Freson K, Hoylaerts M F, Jaeken J, Eyssen M, Arnout J, Vermylen J, Van Geet C
Center for Molecular and Vascular Biology, University Hospital Gasthuisberg, University of Leuven, Belgium.
Thromb Haemost. 2001 Sep;86(3):733-8.
Alternatively spliced GNAS1 and XL-GNAS1, encoding respectively the stimulatory G-protein alpha-subunit (Gsalpha) and the extra-large stimulatory G-protein alpha-subunit (XLsalpha), are located on the imprinted chromosomal region 20q13.12-13. We presently report a functional polymorphism in the imprinted XL-GNAS1 gene. In three patients, a 36 bp insertion and two basepair substitutions flanking this insertion were found in the paternally inherited XL-GNAS1 exon 1. They clinically manifest an enhanced trauma-related bleeding tendency and a variable degree of mental retardation. A platelet aggregation inhibition test to evaluate Gs function was developed. Their platelets display Gs hyperfunction and an enhanced cAMP generation upon stimulation of Gs-coupled receptors. The prevalence of the XLsalpha insertion in a normal control group was 2.2%. Normal controls, inheriting the insertion maternally, had a normal platelet Gs activity, whereas controls inheriting the insertion paternally had increased inducible platelet Gs activity, defining the insertion as a functional polymorphism. This paternally inherited XLsalpha insertion represents a new genetic cause of an inherited bleeding tendency, although to a variable degree.
选择性剪接的GNAS1和XL - GNAS1分别编码刺激性G蛋白α亚基（Gsα）和超大刺激性G蛋白α亚基（XLsα），它们位于印记染色体区域20q13.12 - 13。我们目前报道了印记XL - GNAS1基因中的一种功能多态性。在三名患者中，在父系遗传的XL - GNAS1外显子1中发现了一个36 bp的插入以及该插入两侧的两个碱基对替换。他们临床上表现出与创伤相关的出血倾向增强和不同程度的智力迟钝。开发了一种血小板聚集抑制试验来评估Gs功能。他们的血小板显示出Gs功能亢进，并且在刺激Gs偶联受体时cAMP生成增加。正常对照组中XLsα插入的发生率为2.2%。正常对照组中，母系遗传该插入的个体血小板Gs活性正常，而父系遗传该插入的对照组个体血小板诱导性Gs活性增加，将该插入定义为一种功能多态性。这种父系遗传的XLsα插入代表了遗传性出血倾向的一种新的遗传原因，尽管程度有所不同。
