FBN2 and Associated Diseases
Inherited connective tissue diseases usually affect various systems of the human body. The occurrence of such diseases is related to protein isomerization caused by mutations in the fibrin gene that constitutes connective tissue. Fibrillin-2, encoded by the gene FBN2, is an important building block of connective tissue. FBN2 gene mutation is closely related to hereditary connective tissue diseases, such as congenital contractural arachnodactyly (CCA), macular degeneration (MD), myopathy, and so on. With the goal of helping the scientific research of gene therapy, Creative Biolabs has been deeply cultivating the field of gene therapy research and can provide customers with complete gene therapy research programs and a full range of services.
Function of FBN2
The FBN2 gene is located on the long arm of human chromosome 5 (5q23.3). The length of the gene is 279.57 kb. This gene encodes fibrillin-2 with 2912 amino acid residues and a size of about 350 kDa. Fibrillin-2 consists of an epidermal growth factor-like repeat (EGF), a TGF-β-binding protein repeat (TB), and a hybridization domain (Hyb). The integrity of each domain ensures two key physiological functions of fibrillin-2. First, as an important component of microfibrils, fibrillin-2 is involved in the formation of elastic fibers in connective tissues throughout the body. The normal expression of fibrillin-2 keeps the connective tissue structure intact, thereby maintaining the flexibility of human joints and the development and function of normal organs. Second, fibrillin-2 is involved in the regulation of signaling mediated by members of the TGF-β superfamily. Therefore, mutations in the FBN2 gene can lead to abnormalities in the structure of connective tissue, ultimately leading to disease in multiple organs throughout the body.
Fig.1 Domain organization of fibrillin-1 (FBN1), fibrillin-2 (FBN2), and fibrillin-3 (FBN3). (Peeters, 2022)
Diseases Caused by FBN2 mutations
The missense mutation of the FBN2 gene will change the calcium ion-binding EGF-like domain (cb EGF-like domain), further affecting the three-dimensional structural stability of fibrillin-2, and ultimately making fibrillin-2 more susceptible to hydrolysis. Splicing mutations can cause exon skipping in the open reading frame of the FBN2 gene, thereby affecting the transcription and translation of fibrillin-2, resulting in the shortening of the protein domain or reduced expression of fibrillin-2. The low expression of fibrillin-2 can cause microfibril assembly disorder, and then the structure of the extracellular matrix composed of microfibrils is disordered, thereby disrupting the TGF-β signaling pathway. Ultimately, mutations in the FBN2 gene lead to abnormalities in connective tissue throughout the body. The fragment deletion of the FBN2 gene can cause abnormal development of the newborn's systemic organs, serious complications, and even life-threatening.
Current studies have shown that mutations in the FBN2 gene can lead to CCA, Marfan syndrome, MD, and muscle degeneration. Spider fingers, flexed fingers, and joint contractures develop in adults with CCA. Neonatal CCA patients showed spider-like fingers, polyarticular contractures, ear wrinkling, microjaw deformities, and kyphosis. Marfan syndrome is characterized by slender and uneven limbs, fingers, and toes, and the height is significantly higher than ordinary people. Patients with Marfan syndrome also develop abnormalities of the cardiovascular system, particularly associated heart valve abnormalities and aortic aneurysms. The FBN2 gene plays a key role in the development of the eye. Studies have shown that the reduction of fibrillin-2 in Bruch's membrane caused by FBN2 gene mutation can lead to changes in the ultrastructure of Bruch's membrane, which can lead to macular degeneration. In addition, mutations in the FBN2 gene reduce the elasticity and elongation properties of elastic fibers, resulting in muscle weakness. In addition to the diseases mentioned above, mutations in the FBN2 gene have been found to be associated with atherothrombotic disease, achilles tendinopathy, and rupture of the anterior cruciate ligament.
Fig.2 Photographs of the female patient with biallelic FBN2 variants at the age of 12 and 15 years. (Kloth, 2021)
Interestingly, studies have found that fibrillin-2 in tumor endothelium can promote tumor development by regulating the sequestration of TGF-β by microfibrils, resulting in a higher concentration of TGF-β in the tumor microenvironment. This suggests that the FBN2 gene may be an important target for cancer treatment.
Creative Biolabs has been focusing on the development and application of new biomedical technologies, aiming to provide customers with one-stop gene therapy-related research services. If you have an idea to research FBN2 or other genes, you can contact us at any time to obtain the most comprehensive solutions and services.
References
- Peeters, S.; De, Kinderen P.; et al. The fibrillinopathies: new insights with focus on the paradigm of opposing phenotypes for both FBN1 and FBN2. Human Mutation. 2022, 43(7):815-831.
- Kloth, K.; Neu, A.; et al. Severe congenital contractural arachnodactyly caused by biallelic pathogenic variants in FBN2. The European Journal of Medical Genetics. 2021, 64(3):104161.
