ABCA4 mutations and discordant ABCA4 alleles in patients and siblings with bull's-eye maculopathy
ABCA4 mutations and discordant ABCA4 alleles in patients and siblings with bull's-eye maculopathy
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DOI：
10.1136/bjo.2007.118356
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发表时间：
2007-12-01
影响因子：
4.1
通讯作者：
Webster, A. R.
中科院分区：
文献类型：
--
作者：
Michaelides, M.;Chen, L. L.;Webster, A. R.
目的：为了确定的频率和性质的突变基因ABCA 4在一个队列的患者与牛眼黄斑病变（BEM）：一组49名受试者（包括40先证者/家庭，7兄弟姐妹对和一组三个同胞）BEM，不归因于中毒原因，被确定。从每个病人的血液样本被用来提取基因组DNA，随后的突变筛选的整个编码序列的ABCA 4，使用单链构象多态性（SSCP）分析和直接sequencing.Results：14先证者（35%）被发现有一个潜在的致病ABCA 4序列变异的至少一个等位基因。3例患者有Gly 1961 Glu错义突变，这是Stargardt病（STGD）中最常见的变异，其中2例受试者有黄斑营养不良（MD）表型，另1例ABCA 4变异先前与STGD相关。第二个最常见的STGD突变，Ala 1038 Val，见于1例锥-杆营养不良（CORD）患者。检测到五种新的ABCA 4变体。发现两个兄弟姐妹具有相似的家族内表型，但ABCA 4变异不一致。结论：ABCA 4基因的变异在BEM中很常见。两个兄弟姐妹表现出不一致的ABCA 4变异。这些亲缘关系之一表明，由于ABCA 4疾病等位基因在人群中的高患病率，ABCA 4变体可以在具有另一种分子病因的家族中鉴定。在第二个同胞中明显的不一致性也可能是在患有另一种遗传原因的黄斑疾病的家族中偶然发现的，或者它可能代表由ABCA 4等位基因的组合决定/修饰的复杂遗传模式。
Aim: To determine the frequency and nature of mutations in the gene ABCA4 in a cohort of patients with bull's-eye maculopathy (BEM).Methods: A panel of 49 subjects (comprising 40 probands/families, 7 sibling pairs and a set of three sibs) with BEM, not attributable to toxic causes, was ascertained. Blood samples from each patient were used to extract genomic DNA, with subsequent mutation screening of the entire coding sequence of ABCA4, using single-strand conformational polymorphism (SSCP) analysis and direct sequencing.Results: Fourteen probands (35%) were found to have a potentially disease-causing ABCA4 sequence variant on at least one allele. Three patients had a Gly1961Glu missense mutation, the most common variant in Stargardt disease (STGD), with 2 of these subjects having a macular dystrophy (MD) phenotype and a second ABCA4 variant previously associated with STGD. The second most common STGD mutation, Ala1038Val, was seen in one patient with cone-rod dystrophy (CORD). Five novel ABCA4 variants were detected. Two sibships were identified with a similar intra-familial phenotype but discordant ABCA4 variants.Conclusions: Variations in the ABCA4 gene are common in BEM. Two sibships showed discordant ABCA4 variants. One of these sibships illustrates that ABCA4 variants can be identified in families that have another molecular cause for their disease, due to the high prevalence of ABCA4 disease alleles in the population. The discordance evident in the second sibship may yet also be a chance finding in families with macular disease of another genetic cause, or it may represent a complex mode of inheritance determined/modified by the combination of ABCA4 alleles.