Risk allele of the FZD4 gene for familial exudative vitreoretinopathy
Risk allele of the FZD4 gene for familial exudative vitreoretinopathy
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FZD4 基因的家族性渗出性玻璃体视网膜病变的风险等位基因
DOI：
10.1080/13816810.2017.1401090
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发表时间：
2018
期刊：
影响因子：
1.2
通讯作者：
Higasa K
中科院分区：
文献类型：
--
作者：
Kondo H;Uchio E;Kusaka S;Higasa K
家族性渗出性玻璃体视网膜病变（FEVR）是一种遗传性玻璃体视网膜疾病，其特征是周围视网膜血管发育不全。继发性病理过程导致各种形式的视网膜脱离伴血管生成性增生。导致FEVR的基因是高度异质性的。除了非常罕见的致病基因外，已知FZD 4、LRP 5、TSPAN 12和NDP四个基因引起FEVR。这些基因与WNT信号传导相关，这些基因的突变占FEVR的约50%（1，2）。虽然致病过程被认为是基因的功能障碍，但提前终止突变仅限于约40%，错义突变占约60%的病例（1，2）。一般来说，确定错义突变的致病性是具有挑战性的。导致FEVR的基因突变是私人和罕见的，没有控制。因此，在对照中发现的高频率变异体往往被排除在致病性之外（3）。一个变种，NM_012193。3：c. FZD 4（rs 80358282）的205 C> T（p. H69 Y）首次在一例FEVR日本患者中报告（4）。发现该变异体是FZD 4基因中p.G488D的双重突变，以复合杂合方式分离。由于我们的内部数据显示p.H69Y等位基因在未受影响的个体中的频率为0.67%（n= 150），因此认为p.H69Y是非致病性多态性（4，5）。然而，随后来自日本的一份报告和来自中国的另一份报告显示，5个FEVR家族携带相同的变体（6，7）。值得注意的是，这两名中国患者具有p.E180K或p.W496 * 复合物的FZD 4变体，并且表现出比单一p.H69Y变体携带者更严重的眼部表型（7）。p.H69Y变体的致病性仍不确定（1）。根据国家生物技术信息中心的ClinVar数据库（https//www. ncbi. nlm。gov/clin var，2017年6月访问），但它仍然被归类为“可能良性”。无论对照组中的频率如何，证据表明p.H69Y是致病性的。H69位于高度保守的富含半胱氨酸的结构域的表面。该结构域作为WNT信号传导途径的配体Norrin的结合位点，Norrin是NDP基因的产物。
Familial exudative vitreoretinopathy (FEVR) is a hereditary vitreoretinal disorder characterized by incomplete vascular development in the peripheral retina. The secondary pathological processes lead to various forms of retinal detachments with angiogenic proliferations. The genes causing FEVR are highly heterogeneous. Aside from the very rare causative genes, four genes, FZD4, LRP5, TSPAN12, and NDP, are known to cause FEVR. These genes are related to WNT signaling, and mutations in these genes account for~ 50% of FEVR (1, 2). Although the pathogenic processes are believed to be functional impairments of the genes, premature termination mutations are limited to~ 40% and missense mutations account for~ 60% of the cases (1, 2). In general, the determination of the pathogenicity of missense mutations is challenging. Mutations of the FEVR-causing genes are private and rare with the absence of controls. Thus, the variants that are found at high frequency in controls tend to be rejected from the pathogenicity (3). A variant, NM_012193. 3: c. 205C> T (p. H69Y) of FZD4 (rs80358282) was first reported in a Japanese patient with FEVR (4). This variant was found to be a double mutation with p. G488D in the FZD4 gene segregating in a compound heterozygous manner. Because our in-house data showed a 0.67% frequency of the p. H69Y allele in unaffected individuals (n= 150), p. H69Y was considered to be a nonpathogenic polymorphism (4, 5). However, subsequently one report from Japan and another from China showed that five FEVR families carried the identical variant (6, 7). Notably, the two Chinese patients had FZD4 variants of p. E180K or p. W496* compound heterozygously and showed a more severe ocular phenotype than carriers of a single p. H69Y variant (7). The pathogenicity of the p. H69Y variant remained inconclusive (1). According to the ClinVar database of the National Center for Biotechnology Information (https//www. ncbi. nlm. gov/clin var, June 2017 accessed), it is still categorized as “likely benign.” Regardless of the frequency in controls, lines of evidence indicated that p. H69Y is pathogenic. H69 is located on the surface of the highly conserved cysteine-rich domain. This domain serves as a binding site for the ligand of the WNT signaling pathway, Norrin, a product of the NDP gene.