Novel BMP4 Truncations Resulted in Opposite Ocular Anomalies: Pathologic Myopia Rather Than Microphthalmia

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 datase...

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Autores principales:	Yi Jiang, Jiamin Ouyang, Xueqing Li, Yingwei Wang, Lin Zhou, Shiqiang Li, Xiaoyun Jia, Xueshan Xiao, Wenmin Sun, Panfeng Wang, Qingjiong Zhang
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	pathologic myopia early-onset myopia BMP4 truncation variants microphthalmia Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/b8472fcb5ccb418dbbcf2bcd565a772b
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spelling	oai:doaj.org-article:b8472fcb5ccb418dbbcf2bcd565a772b2021-12-02T01:01:02ZNovel BMP4 Truncations Resulted in Opposite Ocular Anomalies: Pathologic Myopia Rather Than Microphthalmia2296-634X10.3389/fcell.2021.769636https://doaj.org/article/b8472fcb5ccb418dbbcf2bcd565a772b2021-12-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fcell.2021.769636/fullhttps://doaj.org/toc/2296-634XBMP4 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.Yi JiangJiamin OuyangXueqing LiYingwei WangLin ZhouLin ZhouShiqiang LiXiaoyun JiaXueshan XiaoWenmin SunPanfeng WangQingjiong ZhangFrontiers Media S.A.articlepathologic myopiaearly-onset myopiaBMP4truncation variantsmicrophthalmiaBiology (General)QH301-705.5ENFrontiers in Cell and Developmental Biology, Vol 9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	pathologic myopia early-onset myopia BMP4 truncation variants microphthalmia Biology (General) QH301-705.5
spellingShingle	pathologic myopia early-onset myopia BMP4 truncation variants microphthalmia Biology (General) QH301-705.5 Yi Jiang Jiamin Ouyang Xueqing Li Yingwei Wang Lin Zhou Lin Zhou Shiqiang Li Xiaoyun Jia Xueshan Xiao Wenmin Sun Panfeng Wang Qingjiong Zhang Novel BMP4 Truncations Resulted in Opposite Ocular Anomalies: Pathologic Myopia Rather Than Microphthalmia
description	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.
format	article
author	Yi Jiang Jiamin Ouyang Xueqing Li Yingwei Wang Lin Zhou Lin Zhou Shiqiang Li Xiaoyun Jia Xueshan Xiao Wenmin Sun Panfeng Wang Qingjiong Zhang
author_facet	Yi Jiang Jiamin Ouyang Xueqing Li Yingwei Wang Lin Zhou Lin Zhou Shiqiang Li Xiaoyun Jia Xueshan Xiao Wenmin Sun Panfeng Wang Qingjiong Zhang
author_sort	Yi Jiang
title	Novel BMP4 Truncations Resulted in Opposite Ocular Anomalies: Pathologic Myopia Rather Than Microphthalmia
title_short	Novel BMP4 Truncations Resulted in Opposite Ocular Anomalies: Pathologic Myopia Rather Than Microphthalmia
title_full	Novel BMP4 Truncations Resulted in Opposite Ocular Anomalies: Pathologic Myopia Rather Than Microphthalmia
title_fullStr	Novel BMP4 Truncations Resulted in Opposite Ocular Anomalies: Pathologic Myopia Rather Than Microphthalmia
title_full_unstemmed	Novel BMP4 Truncations Resulted in Opposite Ocular Anomalies: Pathologic Myopia Rather Than Microphthalmia
title_sort	novel bmp4 truncations resulted in opposite ocular anomalies: pathologic myopia rather than microphthalmia
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/b8472fcb5ccb418dbbcf2bcd565a772b
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Novel BMP4 Truncations Resulted in Opposite Ocular Anomalies: Pathologic Myopia Rather Than Microphthalmia

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