Gold-von Simson Gabrielle, Leyne Maire, Mull James, Rolnitzky Linda M, Goldberg Judith D, Berlin Dena, Axelrod Felicia B, Slaugenhaupt Susan A
Department of Pediatrics, New York University School of Medicine, New York, New York 10016, USA.
Pediatr Res. 2008 Feb;63(2):186-90. doi: 10.1203/PDR.0b013e31815ef74b.
The common familial dysautonomia (FD) mutation results in tissue specific mis-splicing with reduced amount of wild-type (WT) IkappaB kinase associated protein gene (IKBKAP) mRNA and ELP1. ELP1 is a subunit of Elongator, formerly called the IkappaB kinase associated protein (IKAP) protein. We measured IKBKAP mRNA in peripheral blood leukocytes to determine whether FD subjects and carriers have characteristic levels. Estimated mean IKBKAP mRNA levels, measured by quantitative PCR and expressed as amount relative to the noncarrier average, were significantly different for the two groups when not adjusted for age and sex (p < 0.001): FD subjects 0.23, 95% confidence interval (CI) (0.19, 0.28); carriers 0.58, 95% CI (0.50, 0.68); or adjusted for age and sex (p < 0.001): FD subjects 0.21, 95% CI (0.16, 0.26); carriers 0.66, 95% CI (0.55, 0.79). Comparison of IKBKAP mRNA levels of the 22 FD subjects and their related carriers showed a strong correlation, providing evidence for genetic control of splicing efficiency. IKBKAP mRNA levels were not higher in those subjects using tocotrienols or epigallocatechin gallate. Levels of IKBKAP mRNA in peripheral blood leukocytes can be used to assess molecular response to therapies aimed at enhancing exon 20 inclusion and increasing cellular levels of ELP1/IKAP.
常见的家族性自主神经功能障碍（FD）突变导致组织特异性剪接错误，野生型（WT）IκB激酶相关蛋白基因（IKBKAP）mRNA和ELP1的量减少。ELP1是Elongator的一个亚基，以前称为IκB激酶相关蛋白（IKAP）。我们测量了外周血白细胞中的IKBKAP mRNA，以确定FD患者和携带者是否具有特征性水平。通过定量PCR测量并以相对于非携带者平均值的量表示的估计平均IKBKAP mRNA水平，在未根据年龄和性别进行调整时，两组之间存在显著差异（p < 0.001）：FD患者为0.23，95%置信区间（CI）（0.19，0.28）；携带者为0.58，95%CI（0.50，0.68）；或根据年龄和性别进行调整后（p < 0.001）：FD患者为0.21，95%CI（0.16，0.26）；携带者为0.66，95%CI（0.55，0.79）。对22名FD患者及其相关携带者的IKBKAP mRNA水平进行比较，显示出很强的相关性，为剪接效率的遗传控制提供了证据。使用生育三烯酚或表没食子儿茶素没食子酸酯的患者中，IKBKAP mRNA水平并未升高。外周血白细胞中IKBKAP mRNA的水平可用于评估针对增强外显子20包含和增加ELP1/IKAP细胞水平的治疗的分子反应。
