Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway
Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway
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DOI：
10.1086/420794
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发表时间：
2004-05-01
影响因子：
9.8
通讯作者：
Byers, PH
中科院分区：
文献类型：
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作者：
Schwarze, U;Hata, RI;Byers, PH
I型胶原的COL 1A 2基因中的剪接位点突变可由于外显子6的部分或完全跳跃而引起Ehlers-Danlos综合征（EDS）的形式，以及由于其它外显子的跳跃而引起轻度、中度或致死形式的成骨不全。我们确定了三个不相关的个人与一种罕见的recorded遗传形式的EDS（特点是关节过度活动，皮肤过度伸展，心脏瓣膜缺陷）;在其中两个，COL 1A 2信使RNA（mRNA）的不稳定性的结果复合杂合性的剪接位点突变的COL 1A 2基因，并在第三，它的结果从纯合性的无义密码子。剪接位点突变导致使用隐蔽剪接供体位点，产生下游提前终止密码子和极不稳定的mRNA。在野生型等位基因中，发生这些突变的两个内含子（IVS 11和IVS 24）通常相对于其各自的直接上游内含子缓慢剪接。在突变等位基因中，上游内含子被去除，因此外显子跳跃不能发生。在IVS 24突变的背景下，计算机生成的围绕突变位点的短段mRNA折叠证明了供体和受体位点之间关系的重新排列，这可能有助于使用隐蔽的供体位点。这些发现表明，内含子去除的顺序是预测剪接位点突变结果的一个重要变量，新生mRNA的折叠可能是决定剪接顺序的一个因素。完全缺乏前α 2（I）链具有产生心脏瓣膜疾病而不累及骨骼的惊人效果。
Splice site mutations in the COL1A2 gene of type I collagen can give rise to forms of Ehlers-Danlos syndrome (EDS) because of partial or complete skipping of exon 6, as well as to mild, moderate, or lethal forms of osteogenesis imperfecta as a consequence of skipping of other exons. We identified three unrelated individuals with a rare recessively inherited form of EDS ( characterized by joint hypermobility, skin hyperextensibility, and cardiac valvular defects); in two of them, COL1A2 messenger RNA (mRNA) instability results from compound heterozygosity for splice site mutations in the COL1A2 gene, and, in the third, it results from homozygosity for a nonsense codon. The splice site mutations led to use of cryptic splice donor sites, creation of a downstream premature termination codon, and extremely unstable mRNA. In the wild-type allele, the two introns (IVS11 and IVS24) in which these mutations occurred were usually spliced slowly in relation to their respective immediate upstream introns. In the mutant alleles, the upstream intron was removed, so that exon skipping could not occur. In the context of the mutation in IVS24, computer-generated folding of a short stretch of mRNA surrounding the mutation site demonstrated realignment of the relationships between the donor and acceptor sites that could facilitate use of a cryptic donor site. These findings suggest that the order of intron removal is an important variable in prediction of mutation outcome at splice sites and that folding of the nascent mRNA could be one element that contributes to determination of order of splicing. The complete absence of proalpha2(I) chains has the surprising effect of producing cardiac valvular disease without bone involvement.