Familial dysautonomia is caused by mutations of the IKAP gene
Familial dysautonomia is caused by mutations of the IKAP gene
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DOI：
10.1086/318808
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发表时间：
2001-03-01
影响因子：
9.8
通讯作者：
Rubin, BY
中科院分区：
文献类型：
--
作者：
Anderson, SL;Coli, R;Rubin, BY
缺陷基因DYS，这是负责家族性自主神经功能障碍（FD），并已被定位到染色体9 q31上的0.5 cM区域，已逃避识别。我们鉴定和表征了来自主要FD单倍型纯合个体的细胞系中由9号染色体的该区域编码的RNA，并且我们观察到编码I κ B激酶复合物相关蛋白（IKAP）的RNA缺乏外显子20，并且由于移码，编码截短的蛋白。序列分析揭示了内含子20的供体剪接位点的T->C转换。在携带次要FD单倍型的个体中，外显子19中的错义突变破坏了共有丝氨酸/苏氨酸激酶磷酸化位点。这种突变导致IKAP磷酸化缺陷。观察到这些突变存在于德系犹太人的随机样本中，大约与FD的预测携带频率相同。这些发现表明编码IKAP的基因突变是FD的原因。
The defective gene DYS, which is responsible for familial dysautonomia (FD) and has been mapped to a 0.5-cM region on chromosome 9q31, has eluded identification. We identified and characterized the RNAs encoded by this region of chromosome 9 in cell lines derived from individuals homozygous for the major FD haplotype, and we observed that the RNA encoding the I kappaB kinase complex-associated protein (IKAP) lacks exon 20 and, as a result of a frameshift, encodes a truncated protein. Sequence analysis reveals a T-->C transition in the donor splice site of intron 20. In individuals bearing a minor FD haplotype, a missense mutation in exon 19 disrupts a consensus serine/threonine kinase phosphorylation site. This mutation results in defective phosphorylation of IKAP. These mutations were observed to be present in a random sample of Ashkenazi Jewish individuals, at approximately the predicted carrier frequency of FD. These findings demonstrate that mutations in the gene encoding IKAP are responsible for FD.