Novel BMP4 Truncations Resulted in Opposite Ocular Anomalies: Pathologic Myopia Rather Than Microphthalmia.
Novel BMP4 Truncations Resulted in Opposite Ocular Anomalies: Pathologic Myopia Rather Than Microphthalmia.
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新型 BMP4 截断导致对侧眼部异常：病理性近视而不是小眼症
DOI：
10.3389/fcell.2021.769636
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发表时间：
2021
影响因子：
5.5
通讯作者：
Zhang Q
中科院分区：
文献类型：
--
作者：
Jiang Y;Ouyang J;Li X;Wang Y;Zhou L;Li S;Jia X;Xiao X;Sun W;Wang P;Zhang Q
据报道，BMP 4变体与综合征性小眼症相关（MCOPS6，OMIM 607932）。本研究旨在描述来自4个中国家庭的8名患者中导致新表型的BMP 4截短突变。在这项研究中，从内部外显子组测序的大型数据集中收集BMP 4变体。通过多种计算机模拟工具以及与来自多个数据库的数据的比较来过滤候选变体。通过桑格测序和共分离分析进一步证实潜在的致病性变体。在7，314名具有不同眼部条件的无关先证者中的4名中检测到BMP 4中的4种新型截短变体。这四个家族中的这四个突变在所有八名患有特定形式的病理性近视的患者中单独共分离，其特征在于显著延长的眼轴长度、后葡萄肿、黄斑斑片状、脉络膜视网膜萎缩、近视性视神经病变或青光眼、玻璃体混浊和独特的外周雪粒视网膜病变。BMP 4中截断的极端罕见性（在gnomAD数据库中被分类为不耐受，pLI = 0.96），这些变体在四个具有病理性近视的家族中的排他性存在，在来自四个家族的八个患者中与相同的特定表型完全共分离的变体，以及在先前的研究中截短的致病性与综合征性小眼症的关联，所有这些都支持BMP 4截短与病理性近视的特定形式的新关联。本研究中提供的数据表明，杂合BMP 4截短导致了一种新的表型：病理性近视而不是小眼症。在其他一些基因如FZD 5和PAX 6中观察到导致高度近视和小眼球的同一基因突变，表明这些基因在早期眼部发育中的双向作用。进一步的研究有望阐明双向调节的分子机制。
BMP4 variants have been reported to be associated with syndromic microphthalmia (MCOPS6, OMIM 607932). This study aims to describe BMP4 truncation mutations contributing to a novel phenotype in eight patients from four Chinese families. In this study, BMP4 variants were collected from a large dataset from in-house exome sequencing. Candidate variants were filtered by multiple in silico tools as well as comparison with data from multiple databases. Potential pathogenic variants were further confirmed by Sanger sequencing and cosegregation analysis. Four novel truncation variants in BMP4 were detected in four out of 7,314 unrelated probands with different eye conditions. These four mutations in the four families solely cosegregated in all eight patients with a specific form of pathologic myopia, characterized by significantly extended axial length, posterior staphyloma, macula patchy, chorioretinal atrophy, myopic optic neuropathy or glaucoma, vitreous opacity, and unique peripheral snow-grain retinopathy. The extreme rarity of the truncations in BMP4 (classified as intolerant in the gnomAD database, pLI = 0.96), the exclusive presence of these variants in the four families with pathologic myopia, variants fully co-segregated with the same specific phenotypes in eight patients from the four families, and the association of the pathogenicity of truncations with syndromic microphthalmia in previous studies, all support a novel association of BMP4 truncations with a specific form of pathologic myopia. The data presented in this study demonstrated that heterozygous BMP4 truncations contributed to a novel phenotype: pathologic myopia rather than microphthalmia. Mutations in the same gene resulting in both high myopia and microphthalmia have been observed for a few other genes like FZD5 and PAX6, suggesting bidirectional roles of these genes in early ocular development. Further studies are expected to elucidate the molecular mechanism of the bidirectional regulation.
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