A comprehensive mutation analysis of RP2 and RPGR in a north American cohort of families with x-linked retinitis pigmentosa
A comprehensive mutation analysis of RP2 and RPGR in a north American cohort of families with x-linked retinitis pigmentosa
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DOI：
10.1086/340848
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发表时间：
2002-06-01
影响因子：
9.8
通讯作者：
Swaroop, A
中科院分区：
文献类型：
--
作者：
Breuer, DK;Yashar, BM;Swaroop, A
X连锁视网膜色素变性（XLRP）是一种临床和遗传异质性视网膜变性疾病。XLRP至少有5个位点已被定位，其中RP 2和RP 3分别占遗传可识别疾病的10%-20%和70%-90%。然而，在各自的基因，RP 2和RPGR的突变，检测到只有10%和20%的家庭与XLRP。在一个选择性剪接的RPGR外显子ORF 15中的突变最近被证明在47个家庭的欧洲队列中占XLRP的60%。我们在一个234个RP家族的北美队列中进行了RP 2和RPGR（包括ORF 15）基因及其5个上游区域的全面筛查。在这些家族中，91个（39%）显示出明确的X连锁遗传，另外88个（38%）显示出与X连锁疾病一致的模式，其余55个（23%）是具有早期发病和/或严重疾病的RP的单纯男性患者。与以前的研究一致，我们发现RP 2基因和原始19个RPGR外显子中的突变被检测到。分别为10%和20%的XLRP先证者。我们的研究显示，在91个X连锁隐性遗传的有据可查的家庭中，有30%的人存在RPGR-ORF 15突变，在分析的234个先证者中，有22%的人存在RPGR-ORF 15突变。我们认为，在该地区尚未表征的RPGR外显子突变，内含子变化，或其他基因可能是该疾病在北美队列的其余部分负责。我们还讨论了我们的研究的遗传诊断，基因型-表型相关性，和基因为基础的治疗的影响。
X-linked retinitis pigmentosa (XLRP) is a clinically and genetically heterogeneous degenerative disease of the retina. At least five loci have been mapped for XLRP; of these, RP2 and RP3 account for 10%-20% and 70%-90% of genetically identifiable disease, respectively. However, mutations in the respective genes, RP2 and RPGR, were detected in only 10% and 20% of families with XLRP. Mutations in an alternatively spliced RPGR exon, ORF15, have recently been shown to account for 60% of XLRP in a European cohort of 47 families. We have performed, in a North American cohort of 234 families with RP, a comprehensive screen of the RP2 and RPGR (including ORF15) genes and their 5 upstream regions. Of these families, 91 (39%) show definitive X-linked inheritance, an additional 88 (38%) reveal a pattern consistent with X-linked disease, and the remaining 55 (23%) are simplex male patients with RP who had an early onset and/or severe disease. In agreement with the previous studies, we show that mutations in the RP2 gene and in the original 19 RPGR exons are detected in ! 10% and 20% of XLRP probands, respectively. Our studies have revealed RPGR-ORF15 mutations in an additional 30% of 91 well-documented families with X-linked recessive inheritance and in 22% of the total 234 probands analyzed. We suggest that mutations in an as-yet-uncharacterized RPGR exon(s), intronic changes, or another gene in the region might be responsible for the disease in the remainder of this North American cohort. We also discuss the implications of our studies for genetic diagnosis, genotype-phenotype correlations, and gene-based therapy.