Homozygosity for a hypomorphic mutation in frizzled class receptor 5 causes syndromic ocular coloboma with microcornea in humans.

IF 3.8 2区 生物学 Q2 GENETICS & HEREDITY
Vianney Cortés-González, Miguel Rodriguez-Morales, Paris Ataliotis, Claudine Mayer, Julie Plaisancié, Nicolas Chassaing, Hane Lee, Jean-Michel Rozet, Florencia Cavodeassi, Lucas Fares Taie
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Abstract

Ocular coloboma (OC) is a congenital disorder caused by the incomplete closure of the embryonic ocular fissure. OC can present as a simple anomaly or, in more complex forms, be associated with additional ocular abnormalities. It can occur in isolation or as part of a broader syndrome, exhibiting considerable genetic heterogeneity. Diagnostic yield for OC remains below 30%, indicating the need for further genetic exploration. Mutations in the Wnt receptor FZD5, which is expressed throughout eye development, have been linked to both isolated and complex forms of coloboma. These mutations often result in a dominant-negative effect, where the mutated FZD5 protein disrupts WNT signaling by sequestering WNT ligands. Here, we describe a case of syndromic bilateral OC with additional features such as microcornea, bone developmental anomalies, and mild intellectual disability. Whole exome sequencing revealed a homozygous rare missense variant in FZD5. Consistent with a loss-of-function effect, overexpressing of fzd5 mRNA harboring the missense variant in zebrafish embryos does not influence embryonic development, whereas overexpression of wild-type fzd5 mRNA results in body axis duplications. However, in vitro TOPFlash assays revealed that the missense variant only caused partial loss-of-function, behaving as a hypomorphic mutation. We further showed that the mutant protein still localized to the cell membrane and maintained proper conformation when modeled in silico, suggesting that the impairment lies in signal transduction. This hypothesis is further supported by the fact that the variant affects a highly conserved amino acid known to be crucial for protein-protein interactions.

frizzled 类受体 5 的同基因低态突变会导致人类眼部黑瘤伴小角膜综合征。
眼裂畸形(OC)是一种先天性疾病,由胚胎眼裂闭合不全引起。OC 可表现为简单的异常,或在更复杂的情况下,与其他眼部异常相关联。它可以单独发生,也可以作为更广泛的综合征的一部分,表现出相当大的遗传异质性。OC 的诊断率仍低于 30%,这表明需要进一步的遗传学探索。Wnt 受体 FZD5 在整个眼球发育过程中都有表达,它的突变与孤立型和复杂型巨眼病都有关联。这些突变通常会导致显性阴性效应,即突变的 FZD5 蛋白会通过封闭 WNT 配体来破坏 WNT 信号转导。在此,我们描述了一例综合征双侧 OC 病例,该病例还伴有小角膜、骨骼发育异常和轻度智力障碍等其他特征。全外显子组测序发现了 FZD5 的同卵罕见错义变异。与功能缺失效应一致的是,在斑马鱼胚胎中过表达含有该错义变体的 fzd5 mRNA 不会影响胚胎发育,而过表达野生型 fzd5 mRNA 则会导致体轴重复。然而,体外 TOPFlash 试验显示,该错义变体仅导致部分功能缺失,表现为低态突变。我们还进一步发现,突变体蛋白仍然定位在细胞膜上,并且在进行硅建模时保持正确的构象,这表明其功能障碍在于信号转导。该变异影响了一个高度保守的氨基酸,而已知该氨基酸对蛋白质之间的相互作用至关重要,这一事实进一步支持了这一假设。
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来源期刊
Human Genetics
Human Genetics 生物-遗传学
CiteScore
10.80
自引率
3.80%
发文量
94
审稿时长
1 months
期刊介绍: Human Genetics is a monthly journal publishing original and timely articles on all aspects of human genetics. The Journal particularly welcomes articles in the areas of Behavioral genetics, Bioinformatics, Cancer genetics and genomics, Cytogenetics, Developmental genetics, Disease association studies, Dysmorphology, ELSI (ethical, legal and social issues), Evolutionary genetics, Gene expression, Gene structure and organization, Genetics of complex diseases and epistatic interactions, Genetic epidemiology, Genome biology, Genome structure and organization, Genotype-phenotype relationships, Human Genomics, Immunogenetics and genomics, Linkage analysis and genetic mapping, Methods in Statistical Genetics, Molecular diagnostics, Mutation detection and analysis, Neurogenetics, Physical mapping and Population Genetics. Articles reporting animal models relevant to human biology or disease are also welcome. Preference will be given to those articles which address clinically relevant questions or which provide new insights into human biology. Unless reporting entirely novel and unusual aspects of a topic, clinical case reports, cytogenetic case reports, papers on descriptive population genetics, articles dealing with the frequency of polymorphisms or additional mutations within genes in which numerous lesions have already been described, and papers that report meta-analyses of previously published datasets will normally not be accepted. The Journal typically will not consider for publication manuscripts that report merely the isolation, map position, structure, and tissue expression profile of a gene of unknown function unless the gene is of particular interest or is a candidate gene involved in a human trait or disorder.
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