Salameh Manar, Abu Tair Ghadeer, Mousa Samira, Obolensky Alexey, Swaroop Anand, Roosing Susanne, Mezer Eedy, Soudry Shiri, Karali Marianthi, Simonelli Francesca, Banfi Sandro, Banin Eyal, Ben-Yosef Tamar, Sharon Dror, Khateb Samer
Department of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, the Hebrew University of Jerusalem, Jerusalem, Israel.
Neurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, Bethesda, Maryland.
JAMA Ophthalmol. 2025 Jul 17. doi: 10.1001/jamaophthalmol.2025.2187.
Uncovering the genetic basis of inherited retinal diseases (IRDs) can enhance both diagnostic accuracy and the development of targeted treatment strategies.
To evaluate the association between a homozygous nonsense variant in CREB3 with IRDs.
DESIGN, SETTING, AND PARTICIPANTS: Thirteen patients with a clinical diagnosis of retinitis pigmentosa or cone-rod degeneration were analyzed by whole-genome sequencing (WGS) and whole-exome sequencing (WES). Clinically, patients presented with 2 main phenotypes, rod-cone and cone-rod dystrophies, demonstrating variable electrophysiological and fundoscopic findings. Expression analysis was performed on patient-derived skin fibroblasts using the reverse transcription-polymerase chain reaction and Western blot analysis, and by interrogating previously published retinal single-cell RNA sequence data. Immunohistochemistry staining was performed on wild-type mouse retinal sections using an anti-CREB3 antibody. Patients with variable phenotypes of IRDs were recruited from 3 medical centers in Israel and Italy. Ophthalmologists clinically diagnosed patients at the relevant medical centers and referred them for genetic screening. WES and WGS were performed at different national and international centers, and the findings of the previously unreported gene were shared between investigators.
CREB3 and IRDs.
The main outcome was evidence supporting an association between CREB3 and IRD. Measures included WES, WGS, and immunohistochemistry staining.
A founder homozygous nonsense variant in CREB3 (c.881G>A, p.Trp294*) was identified in 13 patients from 4 unrelated families; 12 descendent from North-African Jewish origins and 1 from Italian origins. All patients manifested retinal degeneration with varying ages at onset. In patient-derived fibroblasts, the variant mRNA transcript generated a truncated CREB3 protein. Expression analysis and immunohistochemistry staining revealed CREB3 RNA and protein expression in various retinal cell types, indicating its vital role in photoreceptor function.
This study found an association between CREB3 and IRDs. CREB3 was previously shown to be upregulated following ultraviolet radiation. This might contribute to the extensive clinical variability observed in this relatively large cohort of homozygous patients with the same truncated variant.
揭示遗传性视网膜疾病（IRD）的遗传基础可提高诊断准确性并推动靶向治疗策略的发展。
评估CREB3基因纯合无义变异与IRD之间的关联。
设计、背景和参与者：对13例临床诊断为色素性视网膜炎或锥杆营养不良的患者进行全基因组测序（WGS）和全外显子组测序（WES）。临床上，患者表现出两种主要表型，即视杆 - 视锥和视锥 - 视杆营养不良，具有不同的电生理和眼底镜检查结果。使用逆转录 - 聚合酶链反应和蛋白质免疫印迹分析对患者来源的皮肤成纤维细胞进行表达分析，并通过查询先前发表的视网膜单细胞RNA序列数据进行分析。使用抗CREB3抗体对野生型小鼠视网膜切片进行免疫组织化学染色。IRD不同表型的患者来自以色列和意大利的3个医疗中心。眼科医生在相关医疗中心对患者进行临床诊断，并将他们转诊进行基因筛查。WES和WGS在不同的国内和国际中心进行，研究人员之间共享了先前未报道基因的研究结果。
CREB3和IRD。
主要结局是支持CREB3与IRD之间存在关联的证据。测量指标包括WES、WGS和免疫组织化学染色。
在来自4个无关家族的13例患者中鉴定出CREB3基因的一个始祖纯合无义变异（c.881G>A，p.Trp294*）；其中12例为北非犹太裔后裔，1例为意大利裔。所有患者均表现出视网膜变性，发病年龄各异。在患者来源的成纤维细胞中，变异的mRNA转录本产生了截短的CREB3蛋白。表达分析和免疫组织化学染色显示CREB3 RNA和蛋白质在各种视网膜细胞类型中表达，表明其在光感受器功能中起着至关重要的作用。
本研究发现CREB3与IRD之间存在关联。先前研究表明CREB3在紫外线辐射后会上调。这可能导致在这一相对较大的具有相同截短变异的纯合患者队列中观察到广泛的临床变异性。
