Wiszniewski Wojciech, Zaremba Charles M, Yatsenko Alexander N, Jamrich Milan, Wensel Theodore G, Lewis Richard Alan, Lupski James R
Department of Molecular and Human Genetics, Baylor college of Medicine, Houston, TX 77030, USA.
Hum Mol Genet. 2005 Oct 1;14(19):2769-78. doi: 10.1093/hmg/ddi310. Epub 2005 Aug 15.
ABCA4, also called ABCR, is a retinal-specific member of the ATP-binding cassette (ABC) family that functions in photoreceptor outer segments as a flipase of all-trans retinal. Homozygous and compound heterozygous ABCA4 mutations are associated with various autosomal recessive retinal dystrophies, whereas heterozygous ABCA4 mutations have been associated with dominant susceptibility to age-related macular degeneration in both humans and mice. We analyzed a cohort of 29 arRP families for the mutations in ABCA4 with a commercial microarray, ABCR-400 in addition to direct sequencing and segregation analysis, and identified both mutant alleles in two families (7%): compound heterozygosity for missense (R602W) and nonsense (R408X) alleles and homozygosity for a complex [L541P; A1038V] allele. The missense mutations were analyzed functionally in the photoreceptors of Xenopus laevis tadpoles, which revealed mislocalization of ABCA4 protein. These mutations cause retention of ABCA4 in the photoreceptor inner segment, likely by impairing correct folding, resulting in the total absence of physiologic protein function. Patients with different retinal dystrophies harboring two misfolding alleles exhibit early age-of-onset (AO) (5-12 years) of retinal disease. Our data suggest that a class of ABCA4 mutants may be an important determinant of the AO of disease.
ABCA4，也称为ABCR，是ATP结合盒（ABC）家族的视网膜特异性成员，在光感受器外段作为全反式视黄醛的翻转酶发挥作用。纯合子和复合杂合子ABCA4突变与各种常染色体隐性视网膜营养不良有关，而杂合子ABCA4突变在人类和小鼠中均与年龄相关性黄斑变性的显性易感性有关。我们使用商业微阵列ABCR-400以及直接测序和分离分析，分析了29个常染色体隐性视网膜色素变性（arRP）家族中的ABCA4突变，在两个家族（7%）中鉴定出了两个突变等位基因：错义（R602W）和无义（R408X）等位基因的复合杂合性以及复合[L541P；A1038V]等位基因的纯合性。对非洲爪蟾蝌蚪光感受器中的错义突变进行了功能分析，结果显示ABCA4蛋白定位错误。这些突变可能通过损害正确折叠导致ABCA4在光感受器内段滞留，从而导致生理蛋白功能完全缺失。携带两个错误折叠等位基因的不同视网膜营养不良患者表现出视网膜疾病的早发（5 - 12岁）。我们的数据表明，一类ABCA4突变体可能是疾病早发的重要决定因素。
