Homozygosity for a novel ABCA4 founder splicing mutation is associated with progressive and severe stargardt-like disease
Homozygosity for a novel ABCA4 founder splicing mutation is associated with progressive and severe stargardt-like disease
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DOI：
10.1167/iovs.07-0244
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发表时间：
2007-09-01
影响因子：
4.4
通讯作者：
Sharon, Dror
中科院分区：
文献类型：
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作者：
Beit-Ya'acov, Anat;Mizrahi-Meissonnier, Liliana;Sharon, Dror
目的。对居住在同一村庄的6个表现出罕见视网膜变性的家庭成员进行临床特征和遗传分析。眼科检查包括全面的临床检查、视力检查、色觉测试和视网膜电图。利用微阵列分析和直接测序技术筛选ABCA4基因突变。采用RT-PCR进行RNA分析并测序。作者招募了15名患有一种独特视网膜疾病的患者，他们来自同一个村庄的6个高度近亲的阿拉伯-穆斯林家庭。在疾病早期，眼底和血管造影的发现以及视网膜功能与Stargardt病相似。然而，在以后的生活中，严重的，广泛的锥杆退化随之而来。明显的进行性视网膜外周受累将这种表型与典型的Stargardt病区分开来。遗传分析显示ABCA4有两个新的缺失，p. Cys1150del和c. 4254-15del23。1例患者为复合杂合子，表现为典型的Stargardt病。其余14例患者为c. 425415del23内含子缺失纯合子，并呈进行性疾病。我们在所有携带该突变的等位基因中发现了相同的ABCA4单倍型，表明存在始创突变。在正常视网膜和淋巴母细胞样细胞中进行详细的RT-PCR分析，发现全长ABCA4转录物和三种通过选择性剪接产生的新转录物的表达。然而，在受影响的纯合子患者的淋巴母细胞样细胞中无法检测到全长ABCA4转录物。这些结果扩展了ABCA4的基因型-表型相关性，表明新的c. 4254-15del23剪接突变的纯合性与一种严重的进行性疾病有关。
PURPOSE. To clinically characterize and genetically analyze members of six families who reside in the same village and manifest a rare form of retinal degeneration.METHODS. Ophthalmic evaluation included a full clinical examination, perimetry, color vision testing, and electroretinography. Genomic DNA was screened for ABCA4 mutations with the use of microarray analysis and direct sequencing. RNA analysis was performed with RT-PCR and sequencing.RESULTS. The authors recruited 15 patients with a unique retinal disease who are members of six highly consanguineous Arab-Muslim families from a single village. During early stages of disease, funduscopic and angiographic findings as well as retinal function resemble those of Stargardt disease. However, later in life, severe, widespread cone-rod degeneration ensues. Marked progressive involvement of the retinal periphery distinguishes this phenotype from classic Stargardt disease. Genetic analysis of ABCA4 revealed two novel deletions, p. Cys1150del and c. 4254-15del23. One patient, who was a compound heterozygote, manifested typical Stargardt disease. The remaining 14 patients were homozygote for the c. 425415del23 intronic deletion and had the progressive form of disease. We identified an identical ABCA4 haplotype in all alleles carrying this mutation, indicating a founder mutation. Detailed RT-PCR analysis in normal retina and lymphoblastoid cells revealed expression of the full- length ABCA4 transcript and three novel transcripts produced by alternative splicing. The full- length ABCA4 transcript, however, could not be detected in lymphoblastoid cells of affected homozygote patients.CONCLUSIONS. These results expand the genotype-phenotype correlation of ABCA4, showing that homozygosity for the novel c. 4254-15del23 splicing mutation is associated with a severe progressive form of disease.