日前,，北京大學(xué)第三醫(yī)院小兒眼科王樂今教授及四川省人民醫(yī)院楊正林教授領(lǐng)銜的課題組發(fā)現(xiàn)了世界第5個導(dǎo)致先天性眼組織缺損的新基因——ABCB6,，也是我國科學(xué)家首次發(fā)現(xiàn)該疾病致病基因。該研究相關(guān)論文發(fā)表在最新一期《美國人類遺傳學(xué)》（American Journal of Human Genetics）雜志上,。
先天性眼組織缺損是由于胚胎期6周~7周時胚裂閉合不全所導(dǎo)致的一種先天性眼部異常,，多表現(xiàn)為常染色體顯性或隱性遺傳。該病會引起眼球震顫,、視網(wǎng)膜脫離,、視網(wǎng)膜下新生血管等多種并發(fā)癥，從而導(dǎo)致患者視力下降,，甚至致盲,。至今尚無有效的治療方法。
據(jù)了解，ABCB6是繼PAX2,、PAX6,、NKX5-3、SHH 4個致病基因后,，最新被發(fā)現(xiàn)的致病基因,。研究顯示，突變后的ABCB6基因不僅無法維持眼組織發(fā)育所需的金屬離子內(nèi)環(huán)境的穩(wěn)定性,，而且也無法完成向眼組織傳遞正常發(fā)育所需的分子信號,，因此引起胚裂閉合不全，從而導(dǎo)致眼組織缺損的發(fā)生,。課題組不僅發(fā)現(xiàn)該基因的新突變型,，而且通過免疫熒光染色、原位雜交及制作基因敲除動物模型等方法,，對突變的ABCB6基因做了大量的功能研究,，進(jìn)一步驗證了該基因突變后對眼組織缺損的影響。
據(jù)課題專家布娟介紹,，該發(fā)現(xiàn)豐富了先天性眼組織缺損疾病的致病基因庫,，不僅可以增進(jìn)人類對先天性眼組織缺損疾病的認(rèn)識，從而通過產(chǎn)前基因檢測等方法降低出生缺陷,，還能夠為該病的有效防治提供新的研究思路,，為今后進(jìn)行基因治療奠定理論基礎(chǔ)。（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.
