日前,北京大学第三医院小儿眼科王乐今教授及四川省人民医院杨正林教授领衔的课题组发现了世界第5个导致先天性眼组织缺损的新基因——ABCB6,也是我国科学家首次发现该疾病致病基因。该研究相关论文发表在最新一期《美国人类遗传学》(American Journal of Human Genetics)杂志上。
先天性眼组织缺损是由于胚胎期6周~7周时胚裂闭合不全所导致的一种先天性眼部异常,多表现为常染色体显性或隐性遗传。该病会引起眼球震颤、视网膜脱离、视网膜下新生血管等多种并发症,从而导致患者视力下降,甚至致盲。至今尚无有效的治疗方法。
据了解,ABCB6是继PAX2、PAX6、NKX5-3、SHH 4个致病基因后,最新被发现的致病基因。研究显示,突变后的ABCB6基因不仅无法维持眼组织发育所需的金属离子内环境的稳定性,而且也无法完成向眼组织传递正常发育所需的分子信号,因此引起胚裂闭合不全,从而导致眼组织缺损的发生。课题组不仅发现该基因的新突变型,而且通过免疫荧光染色、原位杂交及制作基因敲除动物模型等方法,对突变的ABCB6基因做了大量的功能研究,进一步验证了该基因突变后对眼组织缺损的影响。
据课题专家布娟介绍,该发现丰富了先天性眼组织缺损疾病的致病基因库,不仅可以增进人类对先天性眼组织缺损疾病的认识,从而通过产前基因检测等方法降低出生缺陷,还能够为该病的有效防治提供新的研究思路,为今后进行基因治疗奠定理论基础。(生物谷Bioon.com)
doi:10.1016/j.ajhg.2011.11.026
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ABCB6 mutations cause ocular coloboma
Wang L, He F, Bu J, Liu X, Du W, Dong J, Cooney JD, Dubey SK, Shi Y, Gong B, Li J, McBride PF, Jia Y, Lu F, Soltis KA, Lin Y, Namburi P, Liang C, Sundaresan P, Paw BH, Li DY, Phillips JD, Yang Z.
Ocular coloboma is a developmental defect of the eye and is due to abnormal or incomplete closure of the optic fissure. This disorder displays genetic and clinical heterogeneity. Using a positional cloning approach, we identified a mutation in the ATP-binding cassette (ABC) transporter ABCB6 in a Chinese family affected by autosomal-dominant coloboma. The Leu811Val mutation was identified in seven affected members of the family and was absent in six unaffected members from three generations. A LOD score of 3.2 at θ = 0 was calculated for the mutation identified in this family. Sequence analysis was performed on the ABCB6 exons from 116 sporadic cases of microphthalmia with coloboma (MAC), isolated coloboma, and aniridia, and an additional mutation (A57T) was identified in three patients with MAC. These two mutations were not present in the ethnically matched control populations. Immunostaining of transiently transfected, Myc-tagged ABCB6 in retinal pigment epithelial (RPE) cells showed that it localized to the endoplasmic reticulum and Golgi apparatus of RPE cells. RT-PCR of ABCB6 mRNA in human cell lines and tissue indicated that ABCB6 is expressed in the retinae and RPE cells. Using zebrafish, we show that abcb6 is expressed in the eye and CNS. Morpholino knockdown of abcb6 in zebrafish produces a phenotype characteristic of coloboma and replicates the clinical phenotype observed in our index cases. The knockdown phenotype can be corrected with coinjection of the wild-type, but not mutant, ABCB6 mRNA, suggesting that the phenotypes observed in zebrafish are due to insufficient abcb6 function. Our results demonstrate that ABCB6 mutations cause ocular coloboma.