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FLNB
filamin B
The FLNB gene encodes filamin B, a protein essential for cellular structure, mobility, and the proper development of the skeleton. The FLNB gene provides instructions for making filamin B, a key protein that helps cells maintain their structure and adapt their shape.
FLNB is located on the short (p) arm of chromosome 3, at band 3p14.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The FLNB gene, also known as filamin B, plays a vital role in human biology, primarily through its involvement in cellular architecture and skeletal development. It encodes a protein, filamin B, which is integral to the cytoskeleton-the internal scaffolding of cells that supports shape, movement, and critical cellular processes. Filamin B's functions are particularly crucial during foetal development, where it influences the formation and maturation of cartilage and bone.
Disruptions to the FLNB gene's normal function can lead to a range of developmental disorders, predominantly affecting the skeleton. These conditions underscore the gene's importance in structural biology and developmental pathways.
What the gene does
The filamin B protein, encoded by the FLNB gene, is a critical component of the cytoskeleton, the dynamic network of protein filaments that provides structural support to cells. Filamin B directly binds to actin, a major cytoskeletal protein, facilitating the branching and organisation of actin filaments into a robust network. This interaction is fundamental for cells to maintain their shape, move, and respond to external cues.
Beyond its structural role, filamin B links various cellular proteins to the actin cytoskeleton, influencing cell signalling pathways that are essential for tissue growth and development. It is highly expressed in chondrocytes, the cells responsible for forming cartilage, a flexible tissue vital for early skeletal development. Filamin B contributes to the proliferation and differentiation of chondrocytes, as well as the process of ossification-where cartilage is converted into bone. Its activity is therefore indispensable for proper skeletal formation and maturation, highlighting its diverse involvement in cellular mechanics and developmental biology.
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Chromosome location
The FLNB gene is situated on chromosome 3 in humans, specifically at position 3p14.3. This location on the short arm of chromosome 3 specifies the gene's physical address within the human genome.
Protein structure
The filamin B protein is a large protein composed of 2602 amino acids. Its structural organisation includes several functionally distinct regions and domains. At the N-terminus, an Actin-binding region spanning amino acids 1-239 contains two Calponin-homology domains: Calponin-homology (CH) 1 (amino acids 16-122) and Calponin-homology (CH) 2 (amino acids 139-242). Following this, a Disordered region is found between amino acids 244-267. The protein also features a series of repeated domains, including Filamin 1 (amino acids 249-347), Filamin 2 (amino acids 349-446), Filamin 3 (amino acids 447-543), Filamin 4 (amino acids 544-636), Filamin 5 (amino acids 640-736), Filamin 6 (amino acids 737-839), Filamin 7 (amino acids 840-938), Filamin 8 (amino acids 939-1034), Filamin 9 (amino acids 1035-1127), and Filamin 10 (amino acids 1128-1222). Additionally, a region important for Interaction with FBLP1 is located between amino acids 1128-1511.
Key variants
Variants within the FLNB gene can impact the structure and function of the filamin B protein, leading to a spectrum of inherited conditions. These genetic changes can range from single amino acid substitutions to deletions of protein segments, often resulting in an abnormal protein with altered or atypical functions. The specific location and nature of a gene variant can influence the severity and presentation of the associated condition.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1082G>A | p.Gly361Asp | Pathogenic | ★★☆☆ | Larsen syndrome |
c.1592dup | p.His532fs | Pathogenic/Likely pathogenic | ★★☆☆ | FLNB-related disorder |
c.1740dup | p.Ser581fs | Pathogenic | ★★☆☆ | See cases |
c.1945C>T | p.Arg649Ter | Pathogenic | ★★☆☆ | Spondylocarpotarsal synostosis syndrome |
c.2911dup | p.Ala971fs | Pathogenic/Likely pathogenic | ★★☆☆ | FLNB-related disorder |
c.3583dup | p.Val1195fs | Pathogenic/Likely pathogenic | ★★☆☆ | FLNB-related disorder |
c.4112C>A | p.Ser1371Ter | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.4185C>A | p.Tyr1395Ter | Pathogenic/Likely pathogenic | ★★☆☆ | FLNB-related disorder |
c.4387C>T | p.Arg1463Ter | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.4390+2T>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the FLNB gene are associated with several inherited skeletal dysplasias, conditions primarily affecting bone and cartilage development. These include Atelosteogenesis type 1, Atelosteogenesis type 3, Boomerang dysplasia, Larsen syndrome, and Spondylocarpotarsal synostosis syndrome. Each of these conditions exhibits unique clinical features, although they all stem from disruptions to the normal function of the filamin B protein.
Inheritance pattern
Conditions caused by pathogenic FLNB variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
The FLNB gene is recognised in the UK National Health Service (NHS) Genomic Medicine Service. It is included on several NHS Genomic Test Directories, indicating its clinical relevance for diagnosing specific conditions. These include panels for Arthrogryposis (R83), Clefting, DDG2P, Foetal anomalies (R21), and Skeletal dysplasia (R104), all of which are categorised as 'green' in PanelApp, signifying strong evidence for gene-disease association.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Maintaining a balanced lifestyle, including a nutritious diet and regular physical activity, generally supports overall health. For individuals with conditions related to FLNB gene variants, adherence to medical advice regarding physical therapy and activity levels is especially important to manage symptoms and support skeletal health. It is generally advisable to follow a healthcare professional's recommendations for managing any specific health concerns.
Supplement considerations
There is no conclusive evidence that any specific dietary supplements can prevent or treat conditions associated with FLNB gene variants. Individuals considering supplements should always consult with a healthcare professional to ensure they are safe and appropriate for their specific health needs, as some supplements may interact with medications or have unwanted side effects.
Frequently asked questions
What is the FLNB gene?
The FLNB gene provides instructions for making the filamin B protein, which is crucial for maintaining cell structure and enabling cells to change shape and move. It is particularly important for the development of bone and cartilage.
What conditions are associated with FLNB gene variants?
Variants in the FLNB gene are linked to several inherited skeletal dysplasias, including Atelosteogenesis type 1, Atelosteogenesis type 3, Boomerang dysplasia, Larsen syndrome, and Spondylocarpotarsal synostosis syndrome.
How does the filamin B protein work?
Filamin B interacts with actin to form the cell's cytoskeleton, providing structural support and enabling cell movement. It also plays a role in cell signalling that guides tissue development, especially in cartilage and bone formation.
Where is the FLNB gene located?
The FLNB gene is located on chromosome 3, specifically at position 3p14.3, on the short arm of the chromosome.
Is the FLNB gene included in UK NHS genomic testing?
Yes, the FLNB gene is part of several NHS Genomic Test Directories, including panels for Arthrogryposis, Clefting, Foetal anomalies, and Skeletal dysplasia, reflecting its clinical significance.
References
- Yang CF, Wang CH, Siong H'ng W. Filamin B Loss-of-Function Mutation in Dimerization Domain Causes Autosomal-Recessive Spondylocarpotarsal Synostosis Syndrome with Rib Anomalies. Human mutation. 2017. PMID: 28145000
- Li GH, Kung AW, Huang QY. Common variants in FLNB/CRTAP, not ARHGEF3 at 3p, are associated with osteoporosis in southern Chinese women. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2010. PMID: 19727905
- Wilson SG, Jones MR, Mullin BH. Common sequence variation in FLNB regulates bone structure in women in the general population and FLNB mRNA expression in osteoblasts in vitro. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2009. PMID: 19453265
- Sawyer GM, Clark AR, Robertson SP. Disease-associated substitutions in the filamin B actin binding domain confer enhanced actin binding affinity in the absence of major structural disturbance: Insights from the crystal structures of filamin B actin binding domains. Journal of molecular biology. 2009. PMID: 19505475
- Isidor B, Cormier-Daire V, Le Merrer M. Autosomal dominant spondylocarpotarsal synostosis syndrome: phenotypic homogeneity and genetic heterogeneity. American journal of medical genetics. Part A. 2008. PMID: 18470895
- Bicknell LS, Farrington-Rock C, Shafeghati Y. A molecular and clinical study of Larsen syndrome caused by mutations in FLNB. Journal of medical genetics. 2007. PMID: 16801345
- Zhang D, Herring JA, Swaney SS. Mutations responsible for Larsen syndrome cluster in the FLNB protein. Journal of medical genetics. 2006. PMID: 16648377
- Farrington-Rock C, Firestein MH, Bicknell LS. Mutations in two regions of FLNB result in atelosteogenesis I and III. Human mutation. 2006. PMID: 16752402
- Bicknell LS, Morgan T, Bonafé L. Mutations in FLNB cause boomerang dysplasia. Journal of medical genetics. 2005. PMID: 15994868
- Krakow D, Robertson SP, King LM. Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis. Nature genetics. 2004. PMID: 14991055