Division of Medical Genetics and Genomics, Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
Interdisciplinary Genetics Ph.D. Program, University of Iowa, Iowa City, IA, USA.
Gene Ther. 2022 May;29(5):227-235. doi: 10.1038/s41434-021-00241-1. Epub 2021 Mar 4.
Bardet-Biedl syndrome (BBS) is a rare ciliopathy for which there are no current effective treatments. BBS is a genetically heterogeneous disease, though the M390R mutation in BBS1 is involved in ~25% of all genetic diagnoses of BBS. The principle features of BBS include retinal degeneration, obesity, male infertility, polydactyly, intellectual disability, and renal abnormalities. Patients with mutations in BBS genes often present with night blindness within the first decade of life, which progresses to complete blindness. This is due to progressive loss of photoreceptor cells. Male infertility is caused by a lack of spermatozoa flagella, rendering them immobile. In this study, we have crossed the wild-type human BBS1 gene, driven by the CAG promoter, onto the Bbs1 mouse model to determine if ectopic expression of BBS1 rescues male infertility and retinal degeneration. qRT-PCR indicates that the BBS1 transgene is expressed in multiple tissues throughout the mouse, with the highest expression seen in the testes, and much lower expression in the eye and hypothalamus. Immunohistochemistry of the transgene in the eye showed little if any expression in the photoreceptor outer nuclear layer. When male Bbs1;BBS1 mice are housed with WT females, they are able to sire offspring, indicating that the male infertility phenotype of BBS is rescued by the transgene. Using electroretinography (ERGs) to measure retinal function and optical coherence tomography to measure retinal thickness, we show that the transgene does not confer protection against retinal degeneration in Bbs1;BBS1 mice. The results of this study indicate that the male infertility aspect of BBS is an attractive target for gene therapy.
Bardet-Biedl 综合征（BBS）是一种罕见的纤毛病，目前尚无有效的治疗方法。BBS 是一种遗传异质性疾病，尽管 BBS1 中的 M390R 突变涉及所有 BBS 遗传诊断的约 25％。BBS 的主要特征包括视网膜变性、肥胖、男性不育、多指（趾）畸形、智力残疾和肾脏异常。BBS 基因突变的患者常在生命的第一个十年内出现夜盲症，进而发展为完全失明。这是由于感光细胞逐渐丧失所致。男性不育是由于缺乏精子鞭毛，使其无法移动。在这项研究中，我们将野生型人 BBS1 基因（由 CAG 启动子驱动）转入 Bbs1 小鼠模型中，以确定 BBS1 的异位表达是否可以挽救男性不育和视网膜变性。qRT-PCR 表明 BBS1 转基因在小鼠的多种组织中表达，在睾丸中表达最高，在眼睛和下丘脑中的表达则低得多。转基因在眼睛中的免疫组织化学染色显示，在外核层中的感光细胞中表达很少甚至没有。当雄性 Bbs1;BBS1 小鼠与 WT 雌性小鼠一起饲养时，它们能够生育后代，表明 BBS 的男性不育表型被转基因挽救。通过视网膜电图（ERGs）测量视网膜功能和光学相干断层扫描测量视网膜厚度，我们表明转基因不能预防 Bbs1;BBS1 小鼠的视网膜变性。这项研究的结果表明，BBS 的男性不育方面是基因治疗的一个有吸引力的目标。
