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FERMT1
FERM domain containing kindlin 1
The FERMT1 gene provides instructions for the kindlin-1 protein, which is critical for cell-matrix adhesion, cell proliferation, and cell migration, particularly in epithelial cells. The FERMT1 gene is responsible for producing the kindlin-1 protein, a key component of focal adhesions that link a cell's internal structure to its external environment.
FERMT1 is located on the short (p) arm of chromosome 20, at band 20p12.3. Arm ratio per GRCh38 - banding schematic.
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Clinical tests that include this
Overview
The FERMT1 gene, also known as Kindlin-1, plays a fundamental role in various cellular processes, particularly in epithelial cells that line body surfaces. It is crucial for maintaining the structural integrity of tissues and facilitating cell communication with their surroundings. Understanding FERMT1 is important due to its association with inherited conditions affecting skin and mucous membranes.
What the gene does
The FERMT1 gene provides instructions for synthesising kindlin-1, a protein found within specialised structures called focal adhesions. These focal adhesions act as crucial links between a cell's internal framework (cytoskeleton) and the surrounding network of proteins and molecules (extracellular matrix). Kindlin-1 specifically binds to and activates integrin proteins, which directly connect these internal and external cellular components, facilitating cell-matrix adhesion.
Beyond its structural role, kindlin-1 also helps transmit chemical signals into the cell. This protein is involved in several essential cellular functions, including the growth and division of cells (proliferation) and their movement (migration). In the skin, kindlin-1 is particularly important in keratinocytes, which are the main cells of the epidermis.
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Chromosome location
The FERMT1 gene is situated on chromosome 20 at position p12.3. This location indicates its specific address within the human genome. The gene encodes a protein composed of 677 amino acids.
Protein structure
The kindlin-1 protein, encoded by the FERMT1 gene, contains two notable domains. The FERM (F-actin-binding, Erm/radixin/moesin) domain spans amino acids 96-653. Additionally, a PH (Pleckstrin Homology) domain is located between amino acids 377-473, which is typically involved in binding phosphoinositides and can mediate protein-membrane interactions.
Key variants
Variants in the FERMT1 gene can alter the function of the kindlin-1 protein, potentially disrupting its role in cell adhesion and signalling. These genetic changes can lead to a range of effects on cellular processes, with clinical consequences primarily observed in tissues rich in epithelial cells, such as the skin and mucous membranes.
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.1371+4A>G | - | Pathogenic | ★★☆☆ | Kindler syndrome |
c.328C>T | p.Arg110Ter | Pathogenic | ★★☆☆ | Kindler syndrome |
c.676dup | p.Gln226fs | Pathogenic | ★★☆☆ | Kindler syndrome |
c.811C>T | p.Arg271Ter | Pathogenic | ★★☆☆ | Kindler syndrome |
c.862C>T | p.Arg288Ter | Pathogenic | ★★☆☆ | Kindler syndrome |
c.894G>A | p.Trp298Ter | Pathogenic | ★★☆☆ | not provided |
c.910G>T | p.Glu304Ter | Pathogenic | ★★☆☆ | Kindler syndrome |
c.1051G>T | p.Glu351Ter | Pathogenic | ★☆☆☆ | not provided |
c.1518_1519del | p.Leu508fs | Pathogenic | ★☆☆☆ | not provided |
c.184del | p.Trp62fs | 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 FERMT1 gene are associated with inherited conditions that primarily affect the skin and mucous membranes. The most well-known condition linked to FERMT1 variants is Kindler epidermolysis bullosa, a rare genetic disorder characterised by extremely fragile skin that blisters easily. This condition can also impact the delicate lining of the mouth, eyes, oesophagus, intestines, and genitals.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic FERMT1 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The FERMT1 gene is included in several NHS England Genomic Medicine Service national genomic test directories. It is listed with a 'green' status for COVID-19 research, Epidermolysis bullosa, Epidermolysis bullosa and congenital skin fragility (R164), Infantile enterocolitis & monogenic inflammatory bowel disease, and Primary immunodeficiency or monogenic inflammatory bowel disease (R15), indicating its clinical relevance within these categories.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the FERMT1 gene?
The FERMT1 gene provides instructions for the kindlin-1 protein, which is crucial for cell-matrix adhesion, cell proliferation, and cell migration, particularly in epithelial cells that line body surfaces and cavities.
What condition is associated with variants in the FERMT1 gene?
Variants in the FERMT1 gene are primarily associated with Kindler epidermolysis bullosa, a rare genetic disorder that causes extremely fragile skin and easy blistering, also affecting mucous membranes.
How does the kindlin-1 protein contribute to cell structure?
The kindlin-1 protein is part of focal adhesions, which are structures that link a cell's internal framework (cytoskeleton) to the surrounding extracellular matrix. It activates integrin proteins, directly connecting these components and supporting cell-matrix adhesion.
References
- Margadant C, Kreft M, Zambruno G. Kindlin-1 regulates integrin dynamics and adhesion turnover. PloS one. 2013. PMID: 23776470
- Heinemann A, He Y, Zimina E. Induction of phenotype modifying cytokines by FERMT1 mutations. Human mutation. 2011. PMID: 21309038
- Has C, Castiglia D, del Rio M. Kindler syndrome: extension of FERMT1 mutational spectrum and natural history. Human mutation. 2011. PMID: 21936020
- Lai-Cheong JE, McGrath JA. Kindler syndrome. Dermatologic clinics. 2010. PMID: 19945624
- Herz C, Aumailley M, Schulte C. Kindlin-1 is a phosphoprotein involved in regulation of polarity, proliferation, and motility of epidermal keratinocytes. The Journal of biological chemistry. 2006. PMID: 17012746
- Ashton GH, McLean WH, South AP. Recurrent mutations in kindlin-1, a novel keratinocyte focal contact protein, in the autosomal recessive skin fragility and photosensitivity disorder, Kindler syndrome. The Journal of investigative dermatology. 2004. PMID: 14962093
- Jobard F, Bouadjar B, Caux F. Identification of mutations in a new gene encoding a FERM family protein with a pleckstrin homology domain in Kindler syndrome. Human molecular genetics. 2003. PMID: 12668616
- Siegel DH, Ashton GH, Penagos HG. Loss of kindlin-1, a human homolog of the Caenorhabditis elegans actin-extracellular-matrix linker protein UNC-112, causes Kindler syndrome. American journal of human genetics. 2003. PMID: 12789646