Characterization of large rearrangements in autosomal dominant polycystic kidney disease and the PKD1/TSC2 contiguous gene syndrome.
Characterization of large rearrangements in autosomal dominant polycystic kidney disease and the PKD1/TSC2 contiguous gene syndrome.
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DOI：
10.1038/ki.2008.485
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发表时间：
2008-12
影响因子：
19.6
通讯作者：
Harris, Peter C.
中科院分区：
文献类型：
--
作者：
Consugar, Mark B.;Wong, Wai C.;Lundquist, Patrick A.;Rossetti, Sandro;Kubly, Vickie J.;Walker, Denise L.;Rangel, Laureano J.;Aspinwall, Richard;Niaudet, W. Patrick;Ozen, Seza;David, Albert;Velinov, Milen;Bergstralh, Eric J.;Bae, Kyongtae T.;Chapman, Arlene B.;Guay-Woodford, Lisa M.;Grantham, Jared J.;Torres, Vicente E.;Sampson, Julian R.;Dawson, Brian D.;Harris, Peter C.
大DNA重排约占疾病突变的8%，并且在重复的基因组区域中更为常见，而这些区域很难检测到。常染色体显性多囊肾病 (ADPKD) 是由 PKD1 或 PKD2 突变引起的。 PKD1 位于染色体内重复区域。结节性硬化症基因 TSC2 紧邻 PKD1，大的缺失可导致 PKD1/TSC2 连续基因缺失综合征。为了快速识别大的重排，开发了多重连接依赖性探针扩增测定，利用 PKD1 和六个假基因之间的碱基对差异来生成 PKD1 特异性探针。通过该测定检测了 PKD1、PKD2 和 PKD1/TSC2 中 25 个先前定义的缺失的所有变化，我们还在这些位点发现了 14 个新突变。 CRISP 研究中约 4% 的 ADPKD 患者被发现存在严重重排，这些患者约占碱基对突变阴性家族的三分之一。检测的灵敏度表明，约 40% 的 PKD1/TSC 连续基因缺失综合征家族包含镶嵌病例。本文讨论了发现 PKD1 缺失嵌合体的家族的特征，以说明家族风险和供体选择注意事项。我们的检测方法提高了 ADPKD 患者分子检测的检测水平和可靠性。
Large DNA rearrangements account for about 8% of disease mutations and are more common in duplicated genomic regions, where they are difficult to detect. Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in either PKD1 or PKD2. PKD1 is located in an intrachromosomally duplicated region. A tuberous sclerosis gene, TSC2, lies immediately adjacent to PKD1 and large deletions can result in the PKD1/TSC2 contiguous gene deletion syndrome. To rapidly identify large rearrangements, a multiplex ligation-dependent probe amplification assay was developed employing base-pair differences between PKD1 and the six pseudogenes to generate PKD1-specific probes. All changes in a set of 25 previously defined deletions in PKD1, PKD2 and PKD1/TSC2 were detected by this assay and we also found 14 new mutations at these loci. About 4% of the ADPKD patients in the CRISP study were found to have gross rearrangements, and these accounted for about a third of base-pair mutation negative families. Sensitivity of the assay showed that about 40% of PKD1/TSC contiguous gene deletion syndrome families contained mosaic cases. Characterization of a family found to be mosaic for a PKD1 deletion is discussed here to illustrate family risk and donor selection considerations. Our assay improves detection levels and the reliability of molecular testing of patients with ADPKD.
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