Identifying pathogenic genetic background of simplex or multiplex retinitis pigmentosa patients: a large scale mutation screening study
Identifying pathogenic genetic background of simplex or multiplex retinitis pigmentosa patients: a large scale mutation screening study
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DOI：
10.1136/jmg.2007.056416
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发表时间：
2008-07-01
影响因子：
4
通讯作者：
Kosugi, S.
中科院分区：
文献类型：
--
作者：
Jin, Z-B;Mandai, M.;Kosugi, S.
背景和目的：超过一半的视网膜色素变性(RP)病例是遗传性的单基因或多基因。到目前为止，已鉴定出37个RP的致病基因；然而，在单发或多发的RP患者/家族中，基因缺陷的阐明仍然是有问题的。方法和结果：自2003年以来，我们研究了52例单纯性RP患者，141个多基因RP家系的151例患者，以及6例散发性视网膜变性患者。通过一种基于高效变性高效液相色谱(DHPLC)的分析方法，对30个含有已报道突变的RP致病基因的108个外显子进行筛选。随后对异常片段进行自动测序分析。在28个先证者中发现26个突变，包括2个移码突变、1个氨基酸缺失和23个错义突变，占14.07%。到目前为止，还没有报告18种突变。在两个散发性病例和一个多重家系中发现了不同基因的三对组合突变，表明可能存在新的双基因模式。在23个错义突变中，有21个通过PolyPhen、SIFT、Panther和PMut程序计算预测为有害突变。结论：我们阐明了日本RP患者的突变谱，并证明了利用dHPLC测序的突变检测系统对RP患者进行基因诊断的有效性，这可能为其他与广泛基因连锁的疾病的遗传原因识别提供一种模式策略。
Background and purpose: More than half of the retinitis pigmentosa ( RP) cases are genetically simplex or multiplex. To date, 37 causative genes of RP have been identified; however, the elucidation of gene defects in simplex or multiplex RP patients/families remains problematic. The aim of our study was to identify the genetic causes of RP in patients with unknown or non-Mendelian inheritance.Methods and results: Since 2003, 52 simplex RP patients, 151 patients from 141 multiplex RP families, and six sporadic patients with retinal degeneration were studied. A total of 108 exons of 30 RP-causing genes that harboured the reported mutations were screened by an efficient denaturing high performance liquid chromatography (dHPLC) based assay. Aberrant fragments were subsequently analysed by automatic sequencing. Twenty-six mutations, including two frameshift mutations, one single amino acid deletion, and 23 missense mutations, were identified in 28 probands ( 14.07%). Eighteen mutations have not been reported to date. Three pairs of combined mutations in different genes were identified in two sporadic cases and one multiplex family, indicating the possibility of novel digenic patterns. Of the 23 missense mutations, 21 were predicted as deleterious mutations by computational methods using PolyPhen, SIFT, PANTHER, and PMut programs.Conclusion: We elucidated the mutation spectrum in Japanese RP patients and demonstrated the validity of the mutation detection system using dHPLC sequencing for genetic diagnosis in RP patients independent of familial incidence, which may provide a model strategy for identifying genetic causes in other diseases linked to a wide range of genes.