Founder Effect of a c.828+3A>T Splice Site Mutation in Peripherin 2 (PRPH2) Causing Autosomal Dominant Retinal Dystrophies.
Founder Effect of a c.828+3A>T Splice Site Mutation in Peripherin 2 (PRPH2) Causing Autosomal Dominant Retinal Dystrophies.
复制标题
DOI：
10.1001/jamaophthalmol.2014.6115
复制
发表时间：
2015-05
影响因子：
8.1
通讯作者：
Daiger, Stephen P.
中科院分区：
文献类型：
--
作者：
Shankar, Suma P.;Birch, David G.;Ruiz, Richard S.;Hughbanks-Wheaton, Dianna K.;Sullivan, Lori S.;Bowne, Sara J.;Stone, Edwin M.;Daiger, Stephen P.
对于高度变异性视网膜营养不良家族，应高度重视外周蛋白 2 (PRPH2) 基因中剪接位点突变 c.828+3A>T 的筛查。错误剪接的纠正是一个潜在的治疗目标。旨在确定视网膜营养不良个体中 PRPH2（外周蛋白 2，视网膜变性缓慢）基因供体 c.828+3A>T 突变的患病率、遗传起源和分子机制。德克萨斯大学健康科学中心、爱荷华大学和西南视网膜基金会于 1987 年 1 月 1 日至 2014 年 8 月 1 日期间进行了病例对照研究，研究对象包括来自 200 个诊断为常染色体显性视网膜色素变性的家庭、35 个患有不明黄斑营养不良的家庭和 116 个患有模式营养不良的家庭。通过限制性酶消化、单链构象多态性筛选或双向测序来筛选参与者的 c.828+3A>T 突变。通过变性凝胶电泳或基于毛细管的自动循环测序来确定 PRPH2 基因座侧翼的多态性标记的单倍型和基因内的序列变体。使用剪接预测程序 NetGene2 和外周白细胞非法转录物的逆转录聚合酶链反应分析剪接位点突变对 PRPH2 转录物的影响。剪接位点突变、单倍型和替代转录本的测试结果。在 19 个独立确定的临床诊断为视网膜色素变性、黄斑营养不良和/或型营养不良的家庭的 97 名个体中发现了 PRPH2 突变。所有受影响的个体还共享一个约644 kilobase对的罕见单倍型，包含c.828+3A>T突变，该突变从短串联重复多态性D6S282延伸到PRPH2外显子3中的c.1013G>A（rs434102，单核苷酸多态性），表明该突变来自共同祖先，并且是创始人突变。在诊断为常染色体显性遗传性视网膜色素变性的家庭中，其患病率为 2%，在临床诊断为模式、黄斑和视网膜营养不良的家庭中，患病率为 10%。具有 c.828+3A>T 突变的个体表达了在对照参与者中未发现的 PRPH2 转录本，这与异常剪接一致。 PRPH2 c.828+3A>T 剪接位点突变是遗传性视网膜营养不良的常见原因，并且归因于创始人效应。疾病的可能原因是 PRPH2 信息的错误拼接，导致蛋白质产物被截短。确定遗传病因有助于更准确的管理和未来可能的治疗选择。
Screening for splice site mutation c.828+3A>T in the peripherin 2 (PRPH2) gene should be a high priority in families with highly variable retinal dystrophies. The correction of missplicing is a potential therapeutic target. To determine the prevalence, genetic origin, and molecular mechanism of a donor c.828+3A>T mutation in the PRPH2 (peripherin 2, retinal degeneration slow) gene in individuals with retinal dystrophies. Case-control study that took place at the University of Texas Health Science Center, the University of Iowa, and the Retina Foundation of the Southwest, from January 1, 1987, to August 1, 2014, including affected individuals from 200 families with a diagnosis of autosomal dominant retinitis pigmentosa, 35 families with unspecified macular dystrophies, and 116 families with pattern dystrophy. Participants were screened for the c.828+3A>T mutation by restriction-enzyme digest, single-strand conformational polymorphism screening, or bidirectional sequencing. Haplotypes of polymorphic markers flanking the PRPH2 locus and sequence variants within the gene were determined by denaturing gel electrophoresis or automated capillary-based cycle sequencing. The effect of the splice site mutation on the PRPH2 transcript was analyzed using NetGene2, a splice prediction program and by the reverse transcription polymerase chain reaction of illegitimate transcripts from peripheral white blood cells. Results of testing for splice site mutation, haplotypes, and alternate transcripts. The PRPH2 mutation was found in 97 individuals of 19 independently ascertained families with a clinical diagnosis of retinitis pigmentosa, macular dystrophy, and/or pattern dystrophy. All affected individuals also shared a rare haplotype of approximately 644 kilobase pairs containing the c.828+3A>T mutation, which extends from the short tandem repeat polymorphism D6S282 to c.1013G>A (rs434102, a single-nucleotide polymorphism) in exon 3 of PRPH2, suggesting this mutation is from a common ancestor and is a founder mutation. It has a prevalence of 2% in families diagnosed as having autosomal dominant retinitis pigmentosa and 10% in families with variable clinical diagnosis of pattern, macular, and retinal dystrophies. Individuals with the c.828+3A>T mutation expressed a PRPH2 transcript not found in control participants and that was consistent with abnormal splicing. The PRPH2 c.828+3A>T splice site mutation is a frequent cause of inherited retinal dystrophies and is owing to the founder effect. The likely cause of disease is the missplicing of the PRPH2 message that results in a truncated protein product. Identifying the genetic etiology assists in more accurate management and possible future therapeutic options.
登录
查看更多内容
影响因子：
3.5
作者：
ABADIE, V;JARUZELSKA, J;REY, J
通讯作者：
REY, J
影响因子：
--
作者：
Heon, E;Piguet, B;Stone, EM
通讯作者：
Stone, EM
影响因子：
16.2
作者：
TRAVIS, GH;SUTCLIFFE, JG;BOK, D
通讯作者：
BOK, D
影响因子：
14.9
作者：
Hebsgaard, SM;Korning, PG;Brunak, S
通讯作者：
Brunak, S
影响因子：
30.8
作者：
WELLS, J;WROBLEWSKI, J;BIRD, A
通讯作者：
BIRD, A