A single-base substitution within an intronic repetitive element causes dominant retinitis pigmentosa with reduced penetrance.
A single-base substitution within an intronic repetitive element causes dominant retinitis pigmentosa with reduced penetrance.
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DOI：
10.1002/humu.21071
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发表时间：
2009-09
期刊：
影响因子：
3.9
通讯作者：
Rivolta, Carlo
中科院分区：
文献类型：
--
作者：
Frio, Thomas Rio;McGee, Terri L.;Wade, Nicholas M.;Iseli, Christian;Beckmann, Jacques S.;Berson, Eliot L.;Rivolta, Carlo
我们报告了一个常染色体显性遗传性视网膜色素变性的美国大家族的研究，该视网膜色素变性是一种进行性遗传性视网膜变性。虽然特殊的遗传模式和先前的连锁图谱与PRPF31基因有关，但过去对其所有外显子及其边界的广泛筛查未能发现任何突变。在这项工作中，我们用经典的Sanger方法和超高通量(UHT)测序方法对整个PRPF31基因组区域进行了测序。在已鉴定的众多变异中，位于13号内含子和重复DNA元件内的单碱基替换(c.1374+654C>；G)在所有患者和无症状携带者中都是常见的。这一变化创造了一个新的剪接供体位点，导致两个突变的PRPF31亚型的合成，这些亚型被无义介导的mRNA衰退所降解。结果，我们观察到全长PRPF31的mRNA和蛋白水平总体上降低了，没有证据表明突变蛋白的合成。我们的结果表明，c.1374+654C>；G通过单倍体不足导致视网膜色素变性，类似于目前所描述的绝大多数PRPF31突变。我们讨论了UHT测序技术在突变筛选和持续鉴定深埋在内含子区域内的致病剪接突变方面的潜力。
We report the study of a large American family displaying autosomal dominant retinitis pigmentosa with reduced penetrance, a form of progressive and hereditary retinal degeneration. Although the particular inheritance pattern and previous linkage mapping incriminated the PRPF31 gene, extensive screening of all its exons and their boundaries failed in the past to reveal any mutation. In this work, we sequenced the entire PRPF31 genomic region by both the classical Sanger method and ultra-high throughput (UHT) sequencing. Among the many variants identified, a single-base substitution (c.1374+654C>G) located deep within intron 13 and inside a repetitive DNA element was common to all patients and obligate asymptomatic carriers. This change created a new splice donor site leading to the synthesis of two mutant PRPF31 isoforms, degraded by nonsense-mediated mRNA decay. As a consequence, we observed an overall reduction in full-length PRPF31 mRNA and protein levels, with no evidence of mutant proteins being synthesized. Our results indicate that c.1374+654C>G causes retinitis pigmentosa via haploinsufficiency, similar to the vast majority of PRPF31 mutations described so far. We discuss the potential of UHT sequencing technologies in mutation screening and the continued identification of pathogenic splicing mutations buried deep within intronic regions.
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