脉络膜血症的低形变与导致外显子跳越的新型内含子突变有关。

IF 1.2 4区 医学 Q4 GENETICS & HEREDITY
Ophthalmic Genetics Pub Date : 2024-04-01 Epub Date: 2024-01-26 DOI:10.1080/13816810.2023.2270554
William J Waldock, Laura J Taylor, Sian Sperring, Federica Staurenghi, Cristina Martinez-Fernandez de la Camara, Jennifer Whitfield, Penny Clouston, Imran H Yusuf, Robert E MacLaren
{"title":"脉络膜血症的低形变与导致外显子跳越的新型内含子突变有关。","authors":"William J Waldock, Laura J Taylor, Sian Sperring, Federica Staurenghi, Cristina Martinez-Fernandez de la Camara, Jennifer Whitfield, Penny Clouston, Imran H Yusuf, Robert E MacLaren","doi":"10.1080/13816810.2023.2270554","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>Molecular confirmation of pathogenic sequence variants in the CHM gene is required prior to enrolment in retinal gene therapy clinical trials for choroideremia. Individuals with mild choroideremia have been reported. The molecular basis of genotype-phenotype associations is of clinical relevance since it may impact on selection for retinal gene therapy.</p><p><strong>Methods and materials: </strong>Genetic testing and RNA analysis were undertaken in a patient with mild choroideremia to confirm the pathogenicity of a novel intronic variant in CHM and to explore the mechanism underlying the mild clinical phenotype.</p><p><strong>Results: </strong>A 42-year-old male presented with visual field loss. Fundoscopy and autofluorescence imaging demonstrated mild choroideremia for his age. Genetic analysis revealed a variant at a splice acceptor site in the CHM gene (c.1350-3C > G). RNA analysis demonstrated two out-of-frame transcripts, suggesting pathogenicity, without any detectable wildtype transcripts. One of the two out-of-frame transcripts is present in very low levels in healthy controls.</p><p><strong>Discussion: </strong>Mild choroideremia may result from +3 or -3 splice site variants in CHM. It is presumed that the resulting mRNA transcripts may be partly functional, thereby preventing the development of the null phenotype. Choroideremia patients with such variants may present challenges for gene therapy since there may be residual transcript activity which could result in long-lasting visual function which is atypical for this disease.</p>","PeriodicalId":19594,"journal":{"name":"Ophthalmic Genetics","volume":null,"pages":null},"PeriodicalIF":1.2000,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"A hypomorphic variant of choroideremia is associated with a novel intronic mutation that leads to exon skipping.\",\"authors\":\"William J Waldock, Laura J Taylor, Sian Sperring, Federica Staurenghi, Cristina Martinez-Fernandez de la Camara, Jennifer Whitfield, Penny Clouston, Imran H Yusuf, Robert E MacLaren\",\"doi\":\"10.1080/13816810.2023.2270554\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Introduction: </strong>Molecular confirmation of pathogenic sequence variants in the CHM gene is required prior to enrolment in retinal gene therapy clinical trials for choroideremia. Individuals with mild choroideremia have been reported. The molecular basis of genotype-phenotype associations is of clinical relevance since it may impact on selection for retinal gene therapy.</p><p><strong>Methods and materials: </strong>Genetic testing and RNA analysis were undertaken in a patient with mild choroideremia to confirm the pathogenicity of a novel intronic variant in CHM and to explore the mechanism underlying the mild clinical phenotype.</p><p><strong>Results: </strong>A 42-year-old male presented with visual field loss. Fundoscopy and autofluorescence imaging demonstrated mild choroideremia for his age. Genetic analysis revealed a variant at a splice acceptor site in the CHM gene (c.1350-3C > G). RNA analysis demonstrated two out-of-frame transcripts, suggesting pathogenicity, without any detectable wildtype transcripts. One of the two out-of-frame transcripts is present in very low levels in healthy controls.</p><p><strong>Discussion: </strong>Mild choroideremia may result from +3 or -3 splice site variants in CHM. It is presumed that the resulting mRNA transcripts may be partly functional, thereby preventing the development of the null phenotype. Choroideremia patients with such variants may present challenges for gene therapy since there may be residual transcript activity which could result in long-lasting visual function which is atypical for this disease.</p>\",\"PeriodicalId\":19594,\"journal\":{\"name\":\"Ophthalmic Genetics\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":1.2000,\"publicationDate\":\"2024-04-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Ophthalmic Genetics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/13816810.2023.2270554\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/1/26 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q4\",\"JCRName\":\"GENETICS & HEREDITY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Ophthalmic Genetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/13816810.2023.2270554","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/26 0:00:00","PubModel":"Epub","JCR":"Q4","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
引用次数: 0

摘要

导言:在参加治疗脉络膜血症的视网膜基因治疗临床试验之前,需要对 CHM 基因的致病序列变异进行分子确认。轻度脉络膜血症患者已有报道。基因型与表型关联的分子基础具有临床意义,因为它可能会影响视网膜基因疗法的选择:对一名轻度脉络膜血症患者进行了基因检测和 RNA 分析,以确认 CHM 中一个新型内含子变异的致病性,并探索轻度临床表型的机制:一名42岁的男性患者出现视野缺损。眼底镜检查和自动荧光成像显示,该患者患有与年龄不符的轻度脉络膜血症。基因分析显示,CHM 基因的剪接接受位点存在变异(c.1350-3C > G)。RNA 分析显示有两个框架外转录本,表明存在致病性,但没有检测到任何野生型转录本。这两个失帧转录本中的一个在健康对照组中的含量很低:讨论:轻度脉络膜血症可能源于 CHM 的 +3 或 -3 剪接位点变异。据推测,由此产生的 mRNA 转录本可能具有部分功能,从而避免了无效表型的出现。具有这种变异的脉络膜血症患者可能会给基因治疗带来挑战,因为可能会有残余的转录本活性,从而导致该疾病的非典型的持久视觉功能。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A hypomorphic variant of choroideremia is associated with a novel intronic mutation that leads to exon skipping.

Introduction: Molecular confirmation of pathogenic sequence variants in the CHM gene is required prior to enrolment in retinal gene therapy clinical trials for choroideremia. Individuals with mild choroideremia have been reported. The molecular basis of genotype-phenotype associations is of clinical relevance since it may impact on selection for retinal gene therapy.

Methods and materials: Genetic testing and RNA analysis were undertaken in a patient with mild choroideremia to confirm the pathogenicity of a novel intronic variant in CHM and to explore the mechanism underlying the mild clinical phenotype.

Results: A 42-year-old male presented with visual field loss. Fundoscopy and autofluorescence imaging demonstrated mild choroideremia for his age. Genetic analysis revealed a variant at a splice acceptor site in the CHM gene (c.1350-3C > G). RNA analysis demonstrated two out-of-frame transcripts, suggesting pathogenicity, without any detectable wildtype transcripts. One of the two out-of-frame transcripts is present in very low levels in healthy controls.

Discussion: Mild choroideremia may result from +3 or -3 splice site variants in CHM. It is presumed that the resulting mRNA transcripts may be partly functional, thereby preventing the development of the null phenotype. Choroideremia patients with such variants may present challenges for gene therapy since there may be residual transcript activity which could result in long-lasting visual function which is atypical for this disease.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Ophthalmic Genetics
Ophthalmic Genetics 医学-眼科学
CiteScore
2.40
自引率
8.30%
发文量
126
审稿时长
>12 weeks
期刊介绍: Ophthalmic Genetics accepts original papers, review articles and short communications on the clinical and molecular genetic aspects of ocular diseases.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信