EFEMP1 rare variants cause familial juvenile-onset open-angle glaucoma.
EFEMP1 rare variants cause familial juvenile-onset open-angle glaucoma.
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EFEMP1 罕见变异会导致家族性青少年发病的开角型青光眼。
DOI：
10.1002/humu.24395
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发表时间：
2022
期刊：
影响因子：
3.9
通讯作者：
Levina,
中科院分区：
文献类型：
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作者：
Collantes,EdwardRyanA;Delfin,ManuelS;Fan,Baojian;Torregosa,JustineMayR;Siguan-Bell,Christine;VincentdeGuzmanFlorcruz,Nilo;Martinez,JoseMariaD;JoyMasna-Hidalgo,Barbara;Guzman,VincentPaulT;Anotado-Flores,JewelFaith;Levina,
青少年开角型青光眼（JOAG）是一种严重的青光眼类型，40岁之前发病，呈显性遗传。通过外显子组测序，我们鉴定了来自菲律宾的 3 个独立家族，其具有与疾病共分离的新型 EFEMP1 变体（c.238A>T，p.Asn80Tyr；c.1480T>C，p.Ter494Glnext*29；和 c.1429C>T，p.Arg477Cys）。受影响的变异携带者 (N=≥34) 表现出严重的疾病，平均发病年龄为 16 岁，76% 的人失明。为了研究功能效应，我们用表达三种新型 EFEMP1 变体的载体转染 COS7 细胞，结果表明，与野生型相比，在 JOAG 患者中发现的所有三种变体均引起显着的细胞内蛋白质聚集和保留，也与与其他眼部表型相关的 EFEMP1 变体（包括早发性黄斑变性、Malattia Leventinese/Doyne 蜂窝状视网膜）相比 营养不良。这些结果表明，罕见的EFEMP1编码变异可以通过涉及蛋白质聚集和保留的机制引起JOAG，并且细胞内保留的程度与疾病表型相关。这是 EFEMP1 变异引起 JOAG 的首次报告，扩大了 EFEMP1 疾病谱。我们的结果表明，EFEMP1 突变似乎是菲律宾家庭（一个种族多元化的人群）中相对常见的 JOAG 原因。
Juvenile open‐angle glaucoma (JOAG) is a severe type of glaucoma with onset before age 40 and dominant inheritance. Using exome sequencing we identified 3 independent families from the Philippines with novelEFEMP1variants (c.238A>T, p.Asn80Tyr; c.1480T>C, p.Ter494Glnext*29; and c.1429C>T, p.Arg477Cys) co‐segregating with disease. Affected variant carriers (N= 34) exhibited severe disease with average age of onset of 16 years and with 76% developing blindness. To investigate functional effects, we transfected COS7 cells with vectors expressing the three novelEFEMP1variants and showed that all three variants found in JOAG patients caused significant intracellular protein aggregation and retention compared to wild type and also compared toEFEMP1variants associated with other ocular phenotypes including an early‐onset form of macular degeneration, Malattia Leventinese/Doyne's Honeycomb retinal dystrophy. These results suggest that rareEFEMP1coding variants can cause JOAG through a mechanism involving protein aggregation and retention, and that the extent of intracellular retention correlates with disease phenotype. This is the first report ofEFEMP1variants causing JOAG, expanding theEFEMP1disease spectrum. Our results suggest thatEFEMP1mutations appear to be a relatively common cause of JOAG in Filipino families, an ethnically diverse population.