Huang Shitong, Chen Jiansong, Wang Qiuyu, Zhang Ruyue, Zhuang Jian, Huang Ruiyuan, Yu Changjiang, Fang Miaoxian, Zhao Haishan, Lei Liming
Department of Cardiac Surgical Intensive Care Unit, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China.
Department of Cardiovascular Surgery, Guangdong Provincial People's Hospital's Nanhai Hospital, The Second People's Hospital of Nanhai District Foshan City, Foshan, Guangdong, 528200, China.
BMC Genomics. 2025 Mar 24;26(1):288. doi: 10.1186/s12864-025-11471-7.
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.
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.
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.
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.
马凡综合征（MFS）是一种遗传性常染色体显性疾病，影响结缔组织，发病率约为五千至一万人中有一人。90%的MFS由原纤维蛋白-1（FBN1）基因突变引起。我们在中国南方招募了一个具有MFS表型的家系，并鉴定出一种新的变异。本研究调查了这种基因变异是否具有致病性以及与MFS脂质代谢相关的潜在途径。
招募了一个三代近亲家系进行本研究。对家庭成员进行全外显子组测序（WES）。使用AlphaFold预测蛋白质的三维结构。应用CRISPR/Cas9在斑马鱼中产生类似的fbn1无义突变（fbn1）。对斑马鱼进行RNA测序分析，以确定与MFS发病机制相关的潜在途径。
我们的研究在该家系的FBN1基因中鉴定出一种新的变异[NM_000138.5；c.7764 C＞G：p.（Y2588*）]，并在先证者及其儿子和女儿中鉴定出相同位点的突变。结构建模显示p.Y2588*突变导致蛋白质截短。与野生型斑马鱼相比，F2代fbn1斑马鱼表现出MFS表型。RNA测序分析表明，许多与瘦素相关的基因上调，这可能影响骨骼发育和脂肪稳态。
在FBN1基因中鉴定出一种新的变异。在斑马鱼模型中，我们发现了支持所检测到的无义突变致病性的功能证据。我们的研究提出了脂质代谢与MFS之间关系的一种可能机制。这些发现有助于改善MFS的临床诊断和治疗。
