FLNA and Associated Diseases
Filamin A, encoded by the FLNA gene, is a member of the filamin family. Filamin A is widely expressed in the human body and can interact with a large number of protein factors, participating in cell growth, proliferation, migration, differentiation, and other activities. In particular, the role of FLNA in various genetic diseases has received increasing attention. More and more researchers are researching various cellular activities involved in FLNA. With advanced instruments and mature experience, Creative Biolabs has completed gene-targeting research projects for many customers.
Function of FLNA
FLNA is located on the X chromosome and contains 48 exons. Filamin A, encoded by the FLNA gene, has a molecular weight of 280kD and contains 2647 amino acids. Filamin A is an actin-binding protein composed of two subunits self-linking to form a dimer. Filamin A is similar in structure to the letter V. Each subunit contains an N-terminal actin-binding domain (ABD) and 24 repeating β-sheets. This repeating sheet structure is divided into three parts by two calpain-sensitive regions, namely the rod 1 region, the rod 2 region, and the self-connecting region. The N-terminal actin-binding domain (ABD) consists of CH1 and CH2. The actin-binding sites and chaperone-binding sites on the subunits are involved in various cellular activities such as regulating cell signal transduction and maintaining the cytoskeleton. Maintaining the stability of the cytoskeleton is the primary function of FLNA. Filamin A is bundled with filamentous proteins and linked to the cell membrane through a variety of cell membrane proteins, regulating cytoskeleton rearrangement and cell morphological changes. In terms of cell mechanics and signal transduction, filamin A acts as a scaffold for the binding of various cytoskeletal and signaling proteins. Filamin A attaches intracellular molecules to the cell membrane by binding to transmembrane receptors or ion channels.
Fig.1 Structure of Filamin A. (Zhou, 2021)
FLNA-related diseases
Mutations or fragment deletions in the FLNA gene lead to abnormal splicing of its mRNA or truncated proteins. Cytoskeletal rearrangements of neurons are dysfunctional due to the loss of function of filamin A. This prevents the normal migration of neurons and glial cells to the cerebral cortex and remains in the periventricular compartments, resulting in periventricular nodular heterotopia (PVNH). Interestingly, overexpression of FLNA also inhibits neuronal migration. In humans, mutations in the FLNA gene cause a wide range of clinical disorders. In male embryos, the FLNA gene mutation is lethal, while in female embryos it appears to be of normal intelligence but accompanied by epilepsy. In addition to neurological disorders, patients with FLNA gene mutations are often accompanied by dysplasia of heart valves, lung disease, bone deformities, and coagulation disorders.
Fig.2 Laboratory results of the patient. (Ieda, 2018)
FLNA has a dual role in cancer. When localized in the cytoplasm, filamin A can promote tumor development by binding to various signaling molecules. However, after filamin A is hydrolyzed by Calpain, the remaining C-terminal fragment will be localized in the nucleus. At this point, filamin A can inhibit tumor growth and metastasis by binding to transcription factors. In addition, filamin A can also activate IKKα/NK-κB signaling by regulating the CD28 signaling cascade to regulate apoptosis.
Creative Biolabs has rich experience in the field of gene therapy and has an international advanced nucleic acid technology platform. Our senior professional team can provide customers with a one-stop service. If you have the idea of targeting FLNA to treat diseases, please feel free to contact us to provide you with the fastest plan design and high-quality technical services.
References
- Zhou, J.; Kang, X.; et al. The function and pathogenic mechanism of filamin A. Gene. 2021, 784:145575.
- Ieda, D.; Hori, I.; et al. A novel truncating mutation in FLNA causes periventricular nodular heterotopia, Ehlers-Danlos-like collagenopathy and macrothrombocytopenia. Brain & Development. 2018, 40(6):489-492.
