Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia
Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia
复制标题
DOI：
10.1086/318810
复制
发表时间：
2001-03-01
影响因子：
9.8
通讯作者：
Gusella, JF
中科院分区：
文献类型：
--
作者：
Slaugenhaupt, SA;Blumenfeld, A;Gusella, JF
家族性自主神经功能障碍（FD;也称为“D-D综合征”）是一种德系犹太人疾病，是一组先天性感觉神经病中最著名和最常见的，其特征在于广泛的感觉和可变的自主神经功能障碍。以前，我们已经将FD基因DYS定位到染色体9 q31上的0.5-cM区域，并表明种族偏见是由于奠基者效应，>99.5%的疾病等位基因共享共同的祖先单倍型。为了研究FD的分子基础，我们对FD的最小候选区域进行了测序，并克隆和鉴定了其5个基因。其中之一，IKBKAP，含有两个可以导致FD的突变。主要的单倍型突变位于内含子20的供体剪接位点。这种突变可能导致FD患者mRNA中外显子20的跳跃，尽管他们继续以组织特异性方式表达不同水平的野生型信息。从患者的淋巴母细胞中分离的RNA主要是野生型的，而在从脑中分离的RNA中仅观察到缺失的信息。在4例患者中，与次要单倍型相关的突变是外显子19中的错义（R696 P）突变，预计该突变会破坏潜在的磷酸化位点。我们的研究结果表明，几乎所有FD病例都是由不寻常的剪接缺陷引起的，这种缺陷表现出组织特异性表达;它们也为德系犹太人群体的快速携带者筛查提供了基础。
Familial dysautonomia (FD; also known as "Riley-Day syndrome"), an Ashkenazi Jewish disorder, is the best known and most frequent of a group of congenital sensory neuropathies and is characterized by widespread sensory and variable autonomic dysfunction. Previously, we had mapped the FD gene, DYS, to a 0.5-cM region on chromosome 9q31 and had shown that the ethnic bias is due to a founder effect, with >99.5% of disease alleles sharing a common ancestral haplotype. To investigate the molecular basis of FD, we sequenced the minimal candidate region and cloned and characterized its five genes. One of these, IKBKAP, harbors two mutations that can cause FD. The major haplotype mutation is located in the donor splice site of intron 20. This mutation can result in skipping of exon 20 in the mRNA of patients with FD, although they continue to express varying levels of wild-type message in a tissue-specific manner. RNA isolated from lymphoblasts of patients is primarily wild-type, whereas only the deleted message is seen in RNA isolated from brain. The mutation associated with the minor haplotype in four patients is a missense (R696P) mutation in exon 19, which is predicted to disrupt a potential phosphorylation site. Our findings indicate that almost all cases of FD are caused by an unusual splice defect that displays tissue-specific expression; and they also provide the basis for rapid carrier screening in the Ashkenazi Jewish population.