Functional analysis and classification of homozygous and hypomorphic ABCA4 variants associated with Stargardt macular degeneration.
Functional analysis and classification of homozygous and hypomorphic ABCA4 variants associated with Stargardt macular degeneration.
复制标题
DOI：
10.1002/humu.24100
复制
发表时间：
2020-11
期刊：
影响因子：
3.9
通讯作者：
Molday RS
中科院分区：
文献类型：
--
作者：
Curtis SB;Molday LL;Garces FA;Molday RS
Stargardt黄斑变性（STGD 1）是由编码ABCA 4的基因突变引起的，ABCA 4是一种ATP结合盒蛋白，可跨感光细胞膜转运N-亚视黄基-磷脂酰乙醇胺（N-Ret-PE）。ABCA 4活性降低导致类维生素A积累，导致感光细胞变性。该病的发病和严重程度各不相同，从最初十年的视力严重丧失到晚年的轻度视力损害。我们确定了22种致病错义突变在N-Ret-PE存在和不存在的情况下对ABCA 4表达和ATP酶活性的影响。在STGD 1纯合子个体中发现了与疾病发作相关的三种类型：第1类表现出ABCA 4表达和ATP酶活性降低，但不受N-Ret-PE的刺激;这些变体纯合子个体的疾病发作较早（≤ 13岁）;第2类表现出ATP酶活性降低，但受N-Ret-PE的刺激有限;这些与中度发病（14 - 40岁）相关; 3类显示出高表达和被N-Ret-PE强烈激活的ATP酶活性;这些与晚期发病（> 40岁）相关。基于我们的研究结果，我们引入了一个功能指数来衡量错义突变对STGD 1严重程度的影响。我们的研究支持p.Gly863Ala、p.Asn1868Ile和p.Gly863Ala/p.Asn1868Ile变异体所表现的轻度表型。
Stargardt macular degeneration (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 yr); Class 2 showed reduced ATPase activity with limited stimulation by N-Ret-PE; these correlated with a moderate disease onset (14 – 40 yr); Class 3 displayed high expression and ATPase activity that was strongly activated by N-Ret-PE; these were associated with a late disease onset (> 40 yr). Based on 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.
登录
查看更多内容
影响因子：
3.4
作者：
Burke, Tomas R.;Allikmets, Rando;Tsang, Stephen H.
通讯作者：
Tsang, Stephen H.
影响因子：
3.9
作者：
Cornelis, Stephanie S.;Bax, Nathalie M.;Cremers, Frans P. M.
通讯作者：
Cremers, Frans P. M.
影响因子：
--
作者：
Fishman, GA;Stone, EM;Derlacki, DJ
通讯作者：
Derlacki, DJ
影响因子：
5.3
作者：
Fumagalli, A;Ferrari, M;Cremonesi, L
通讯作者：
Cremonesi, L
影响因子：
2.9
作者：
MACKENZIE, D;ARENDT, A;MOLDAY, RS
通讯作者：
MOLDAY, RS