Fbn2-KO Mouse

Fbn2, the fibrillin-2 gene, encodes products associated with elastin fibres. It is involved in the extracellular matrix organization pathway [5]. Fibrillin-2 is crucial for elastic fiber synthesis, as demonstrated by in vitro studies where hypoxia inhibited elastic fiber synthesis with a reduction in Fbn2 expression at the mRNA and protein levels, and Fbn2 down-regulation was associated with deficient lysyl oxidase maturation [4].

Pathogenic variants in Fbn2 cause congenital contractural arachnodactyly (CCA), an autosomal dominant connective tissue disorder. CCA is characterized by arachnodactyly, camptodactyly, contracture of major joints, scoliosis, pectus deformities, and crumpled ears [1,3,6]. Different Fbn2 pathogenic variants, such as splice-altering (e.g., c.4472-3C>A) and missense (e.g., c.3472G > C) mutations, have been identified in CCA patients, with some variants associated with severe cardiovascular or skeletal manifestations [1,3]. In a Chinese family, co-mutations in COL1A2 and FBN2 genes led to more severe skeletal abnormalities, suggesting a possible synergistic effect between these two genes [5]. In bladder cancer, FBN2 was found to be upregulated and could be an independent prognostic factor, affecting the tumour microenvironment, with its high expression associated with a high stromal score, certain immune cell infiltration patterns, and high sensitivity to some chemotherapy drugs [2]. In fracture studies, FBN2 was identified as a hub gene. It was down-regulated in fracture, and in vitro experiments showed that it promoted the proliferation, mineralization, and differentiation of osteoblasts, accelerating fracture healing [7].

In summary, Fbn2 is essential for elastic fiber synthesis and is involved in multiple biological processes. Its dysfunction, as revealed by studies on genetic variants, is associated with connective tissue disorders like CCA, skeletal abnormalities in cases of co-mutations, bladder cancer progression, and impaired fracture healing. These findings from various research models help understand the role of Fbn2 in specific disease conditions, providing potential directions for diagnosis, genetic counseling, and treatment.

References:

1. Yang, Shulin, Li, Zongzhe. 2024. FBN2 pathogenic variants in congenital contractural arachnodactyly with severe cardiovascular manifestations. In Connective tissue research, 65, 214-225. doi:10.1080/03008207.2024.2340004. https://pubmed.ncbi.nlm.nih.gov/38602424/

2. Lu, Zechao, Lu, Zeguang, Lai, Yongchang, He, Zhaohui, Tang, Fucai. 2023. A comprehensive analysis of FBN2 in bladder cancer: A risk factor and the tumour microenvironment influencer. In IET systems biology, 17, 162-173. doi:10.1049/syb2.12067. https://pubmed.ncbi.nlm.nih.gov/37337404/

3. Huang, Yazhou, Fang, Xingxin, Ma, Linya, Gao, Taoran, Peng, Dan. 2025. FBN2 pathogenic mutation in congenital contractural arachnodactyly with severe skeletal manifestations. In Molecular genetics and metabolism reports, 42, 101193. doi:10.1016/j.ymgmr.2025.101193. https://pubmed.ncbi.nlm.nih.gov/39911746/

4. Boizot, Jérémy, Minville-Walz, Mélaine, Reinhardt, Dieter Peter, Sigaudo-Roussel, Dominique, Debret, Romain. 2022. FBN2 Silencing Recapitulates Hypoxic Conditions and Induces Elastic Fiber Impairment in Human Dermal Fibroblasts. In International journal of molecular sciences, 23, . doi:10.3390/ijms23031824. https://pubmed.ncbi.nlm.nih.gov/35163744/

5. Chen, Jing, Xiang, Qinqin, Xiao, Xiao, Yang, Mei, Liu, Shanling. 2022. Carrying both COL1A2 and FBN2 gene heterozygous mutations results in a severe skeletal clinical phenotype: an affected family. In BMC medical genomics, 15, 154. doi:10.1186/s12920-022-01296-8. https://pubmed.ncbi.nlm.nih.gov/35804365/

6. Sun, Liying, Huang, Yingzhao, Zhao, Sen, Tian, Wen, Wu, Nan. 2022. Identification of Novel FBN2 Variants in a Cohort of Congenital Contractural Arachnodactyly. In Frontiers in genetics, 13, 804202. doi:10.3389/fgene.2022.804202. https://pubmed.ncbi.nlm.nih.gov/35360850/

7. Huang, Jian, Huang, Jun, Li, Nan, Wang, Lanfang, Xiao, Quanhao. 2025. FBN2 promotes the proliferation, mineralization, and differentiation of osteoblasts to accelerate fracture healing. In Scientific reports, 15, 4843. doi:10.1038/s41598-025-89215-6. https://pubmed.ncbi.nlm.nih.gov/39924543/