Identification and functional validation of a novel FBN1 variant in a Marfan syndrome family using a zebrafish model

被引:0
作者
Huang, Shitong [1 ,2 ]
Chen, Jiansong [2 ]
Wang, Qiuyu [3 ]
Zhang, Ruyue [4 ]
Zhuang, Jian [4 ,5 ]
Huang, Ruiyuan [1 ]
Yu, Changjiang [4 ]
Fang, Miaoxian [1 ]
Zhao, Haishan [5 ]
Lei, Liming [1 ,2 ,5 ]
机构
[1] Southern Med Univ, Guangdong Prov Peoples Hosp, Guangdong Cardiovasc Inst, Guangdong Acad Med Sci,Dept Cardiac Surg Intens Ca, Guangzhou 510080, Peoples R China
[2] Peoples Hosp Nanhai Dist Foshan City 2, Guangdong Prov Peoples Hosp Nanhai Hosp, Dept Cardiovasc Surg, Foshan 528200, Guangdong, Peoples R China
[3] Southern Med Univ, Guangdong Prov Peoples Hosp, Guangdong Acad Med Sci, Dept Cardiac Surg Intens Care Unit, Guangzhou 510080, Peoples R China
[4] Southern Med Univ, Guangdong Prov Peoples Hosp, Guangdong Cardiovasc Inst, Guangdong Acad Med Sci,Dept Cardiovasc Surg, Guangzhou 510080, Peoples R China
[5] Southern Med Univ, Guangdong Prov Peoples Hosp, Guangdong Cardiovasc Inst, Guangdong Acad Med Sci,Guangdong Prov Key Lab Sout, Guangzhou 510080, Peoples R China
来源
BMC GENOMICS | 2025年 / 26卷 / 01期
基金
中国国家自然科学基金;
关键词
Marfan syndrome; FBN1; Novel pathogenic variant; Nonsense mutation; Zebrafish; Lipid metabolism; MOUSE MODEL; GENETICS; DISEASE; MATRIX;
D O I
10.1186/s12864-025-11471-7
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Background Marfan syndrome (MFS) is an inherited autosomal dominant disorder that affects connective tissue with an incidence of about 1 in 5,000 to 10,000 people. 90% of MFS is caused by mutations in the fibrillin-1 (FBN1) gene. We recruited a family with MFS phenotype in South China and identified a novel variant. This study investigated whether this genetic variant is pathogenic and the potential pathway related to lipid metabolism in MFS. Methods A three-generation consanguineous family was recruited for this study. Whole exome sequencing (WES) was utilized on family members. The 3D structure of the protein was predicted using AlphaFold. CRISPR/Cas9 was applied to generate a similar fbn1 nonsense mutation (fbn1+/-) in zebrafish. RNA-seq analysis on zebrafish was performed to identify potential pathways related to MFS pathogenesis. Results Our study identified a novel variant [NM_000138.5; c.7764 C > G: p.(Y2588*)] in FBN1 gene from the family and identified the same site mutation among the proband along with her son and daughter. Structural modeling showed the p.Y2588* mutation resulted from a truncated protein. Compared to wild-type zebrafish, the F2 generation fbn1+/- zebrafish exhibited MFS phenotype. RNA-seq analysis indicated that many genes related to leptin are up-regulating, which could affect bone development and adipose homeostasis. Conclusion A novel variant was identified in FBN1 gene. In a zebrafish model, we found functional evidence supporting the pathogenicity of the detected nonsense mutation. Our research proposes a possible mechanism underlying the relationship between lipid metabolism and MFS. These findings can help improve the clinical diagnosis and treatment of MFS.
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页数:19
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