一个类遗传性血小板无力症家系及其分子发病机制研究

OBJECTIVE: To review the clinical characteristics of a pedigree with inherited hemorrhagic disease to explore its molecular pathogenesis. METHODS: The clinical data of the pedigree with inherited hemorrhagic disease were collected. After extracting DNA, next generation sequencing was utilized to detect the potential gene mutation. The changes of RASGRP2 transcript of this proband and his parents were detected using RT-PCR to compare with normal control. RESULTS: The phenotype of the proband in this pedigree with inherited platelet dysfunction and bleeding disorder was similar to variant Glanzmann's thrombasthenia, the maximum aggregations of platelet in response to the physiological agonists including ADP, epinephrine and arachidonic acid were significantly lower, leading to severe spontaneous mucosal bleeding. Integrin αIIbβ3 gene mutation was not detected, but another gene mutation RASGRP2 IVS3-1 stood out. The mutation was homozygous in the proband and heterozygosis in both of his parents. Two transcript types were detected in the proband, without transcripts coding functional RASGRP2 protein, however, his parents had functional transcripts and abnormal transcripts, with the normal transcripts in the majority. CONCLUSION: The RASGRP2 IVS3-1 gene mutation was responsible for the inherited hemorrhagic disease. The RASGRP2 IVS3-1 gene mutation led to abnormal alternative splicing, without formation of functional RASGRP2 protein. The RASGRP2 protein is at the nexus of calcium-dependent platelet activation and hemostasis after damage of blood vessels. Spontaneous mucosal bleeding was a result of the lack of the functional RASGRP2 protein. This was the first report of RASGRP2 gene mutation resulting in bleeding disorder in China, and also the first report of the mutation type of RASGRP2 IVS3-1.