Silva E, Yang J M, Li Y, Dharmaraj S, Sundin O H, Maumenee I H
Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Invest Ophthalmol Vis Sci. 2000 Jul;41(8):2076-9.
To identify and characterize new cone rod homeobox (CRX) mutations associated with the Leber congenital amaurosis phenotype.
The human CRX gene was sequenced in 74 consecutive patients carrying the diagnosis of Leber congenital amaurosis.
Two mutations were identified in CRX that cause frameshifts and predict severe truncations of the encoded protein. One of these, a 1-bp insertion, spares only nine N-terminal amino acids, removing the homeodomain, WSP motif, and conserved OTX domain at the C terminus. Of the CRX mutations described in the literature, this is the first that convincingly represents a null allele of the gene. Although the patient heterozygous for this null allele is affected with Leber congenital amaurosis, it was surprising that her father, who had normal vision, was heterozygous for the same mutation.
These results strongly suggest that haploinsufficiency of CRX is not sufficient to cause a retinal disorder. Loss of function alleles of CRX appear to cause Leber congenital amaurosis through a recessive or multigenic mechanism.
鉴定并表征与莱伯先天性黑蒙表型相关的新的锥杆同源盒（CRX）突变。
对74例连续诊断为莱伯先天性黑蒙的患者的人类CRX基因进行测序。
在CRX中鉴定出两个导致移码并预测编码蛋白严重截短的突变。其中一个是1个碱基对的插入，仅保留9个N端氨基酸，去除了同源结构域、WSP基序和C端保守的OTX结构域。在文献中描述的CRX突变中，这是第一个令人信服地代表该基因无效等位基因的突变。尽管该无效等位基因的杂合子患者患有莱伯先天性黑蒙，但令人惊讶的是，她视力正常的父亲也是该相同突变的杂合子。
这些结果强烈表明，CRX单倍剂量不足不足以导致视网膜疾病。CRX功能丧失等位基因似乎通过隐性或多基因机制导致莱伯先天性黑蒙。
