Nat Gene：NMNAT1基因引发一种罕见早期失明LCA

近日，来自费城儿童医院都研究机构的研究者发现了一种新的基因，该基因可以促使常见的先天性利伯氏黑蒙（LCA）-一种非常罕见，极具破坏力的早期失明。新的LCA基因名为NMNAT1，发现该基因对于将来治疗失明患者无疑是一大惊喜。相关研究成果刊登在国际著名杂志Nature Genetics上。

LCA是一种遗传性的视网膜退行性疾病，在婴儿期便开始发病时的婴儿的视力下降。NMNAT1基因是第18个被识别的LCA相关基因。在识别NMNAT1的过程中，研究者使用了全基因组测序的方法来进行筛选，最终发现了和LCA相关的基因NMNAT1。

尽管已知的和LCA相关的基因都参与了眼睛检测光的视黄醛蛋白质的功能障碍过程，然而

NMNAT1基因是第一个和LCA相关的代谢酶，研究者目前的疑问是NMNAT1的突变是否可以引发其它地区LCA病人发病，筛选了284个来自美国、英国和法国等国的LCA病人，这将允许研究者继续深入研究。

研究者指出，早期的LCA-NMNAT1病人治疗较为有益，而且NMNAT1突变的年轻病人易于损伤视网膜中心，这将影响中央视觉。

编译自：Elusive Gene That Causes a Form of Blindness from Birth Dlscovered

doi:10.1038/ng.2361
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NMNAT1 mutations cause Leber congenital amaurosis

Marni J Falk,1, 2, 22 Qi Zhang,3, 4, 22 Eiko Nakamaru-Ogiso,5 Chitra Kannabiran,6 Zoe Fonseca-Kelly,3, 4 Christina Chakarova,7 Isabelle Audo,8, 9, 10, 11 Donna S Mackay,7 Christina Zeitz,8, 9, 10 Arundhati Dev Borman,7, 12 Magdalena Staniszewska,3, 4 Rachna Shukla,6 Lakshmi Palavalli,6 Saddek Mohand-Said,8, 9, 10, 11 Naushin H Waseem,7 Subhadra Jalali,6, 13 Juan C Perin,14 Emily Place,1, 3, 4 Julian Ostrovsky,1 Rui Xiao,15 Shomi S Bhattacharya,7, 16 Mark Consugar,3, 4 Andrew R Webster,7, 12 José-Alain Sahel,8, 9, 10, 11, 17, 18 Anthony T Moore,7, 12, 19 Eliot L Berson,4 Qin Liu,3, 4 Xiaowu Gai20, 21, 23 & Eric A Pierce3, 4, 23 et al.

Leber congenital amaurosis (LCA) is an infantile-onset form of inherited retinal degeneration characterized by severe vision loss1, 2. Two-thirds of LCA cases are caused by mutations in 17 known disease-associated genes3 (Retinal Information Network (RetNet)). Using exome sequencing we identified a homozygous missense mutation (c.25G>A, p.Val9Met) in NMNAT1 that is likely to be disease causing in two siblings of a consanguineous Pakistani kindred affected by LCA. This mutation segregated with disease in the kindred, including in three other children with LCA. NMNAT1 resides in the previously identified LCA9 locus and encodes the nuclear isoform of nicotinamide mononucleotide adenylyltransferase, a rate-limiting enzyme in nicotinamide adenine dinucleotide (NAD+) biosynthesis4, 5. Functional studies showed that the p.Val9Met alteration decreased NMNAT1 enzyme activity. Sequencing NMNAT1 in 284 unrelated families with LCA identified 14 rare mutations in 13 additional affected individuals. These results are the first to link an NMNAT isoform to disease in humans and indicate that NMNAT1 mutations cause LCA.