Functional analysis and classification of homozygous and hypomorphic ABCA4 variants associated with Stargardt macular degeneration.,Human Mutation

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Functional analysis and classification of homozygous and hypomorphic ABCA4 variants associated with Stargardt macular degeneration.
Human Mutation ( IF 3.3 ) Pub Date : 2020-08-26 , DOI: 10.1002/humu.24100
Susan B Curtis ₁ , Laurie L Molday ₁ , Fabian A Garces ₁ , Robert S Molday _{1,

2}

Affiliation

Stargardt macular degeneration (Stargardt disease 1 [STGD1]) is caused by mutations in the gene encoding ABCA4, an ATP‐binding cassette protein that transports N‐retinylidene‐phosphatidylethanolamine (N‐Ret‐PE) across photoreceptor membranes. Reduced ABCA4 activity results in retinoid accumulation leading to photoreceptor degeneration. The disease onset and severity vary from severe loss in visual acuity in the first decade to mild visual impairment late in life. We determined the effect of 22 disease‐causing missense mutations on the expression and ATPase activity of ABCA4 in the absence and presence of N‐Ret‐PE. Three classes were identified that correlated with the disease onset in homozygous STGD1 individuals: Class 1 exhibited reduced ABCA4 expression and ATPase activity that was not stimulated by N‐Ret‐PE; individuals homozygous for these variants had an early disease onset (≤13 years); Class 2 showed reduced ATPase activity with limited stimulation by N‐Ret‐PE; these correlated with moderate disease onset (14–40 years); and Class 3 displayed high expression and ATPase activity that was strongly activated by N‐Ret‐PE; these were associated with late disease onset (>40 years). On the basis of our results, we introduce a functionality index for gauging the effect of missense mutations on STGD1 severity. Our studies support the mild phenotype exhibited by the p.Gly863Ala, p.Asn1868Ile, and p.Gly863Ala/p.Asn1868Ile variants.

中文翻译：

与 Stargardt 黄斑变性相关的纯合子和亚形 ABCA4 变体的功能分析和分类。

Stargardt 黄斑变性（Stargardt 病 1 [STGD1]）是由编码 ABCA4 的基因突变引起的，ABCA4 是一种 ATP 结合盒蛋白，可将N-视黄基-磷脂酰乙醇胺 ( N -Ret-PE) 跨过光感受器膜。ABCA4 活性降低导致类视色素积累，导致光感受器变性。疾病的发作和严重程度从最初十年的视力严重丧失到生命后期的轻度视力损害不等。我们确定了在N不存在和存在的情况下 22 种引起疾病的错义突变对 ABCA4 表达和 ATPase 活性的影响-Ret-PE。确定了与纯合 STGD1 个体的疾病发作相关的三类：第 1 类表现出 ABCA4 表达和 ATPase 活性降低，不受N -Ret-PE刺激；这些变异纯合子的个体发病较早（≤13 岁）；2 类显示在N -Ret-PE有限刺激下 ATP 酶活性降低；这些与中度发病（14-40 岁）相关；和 Class 3 表现出高表达和 ATPase 活性，被N强烈激活-Ret-PE；这些与晚期发病（> 40 岁）有关。根据我们的结果，我们引入了一个功能指数，用于衡量错义突变对 STGD1 严重程度的影响。我们的研究支持 p.Gly863Ala、p.Asn1868Ile 和 p.Gly863Ala/p.Asn1868Ile 变体表现出的轻度表型。

更新日期：2020-10-30

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