Filaggrin
Encyclopedia
Filaggrin is a filament-associated protein
that binds to keratin
fibers in epithelial cell
s.
. Profilaggrin undergoes proteolytic
processing to yield individual filaggrin monomers at the transition between the stratum granulosum
and the stratum corneum
, which may be facilitated by calcium
-dependant enzymes.
, filaggrin monomers can become incorporated into the lipid envelope, which is responsible for the skin barrier function. Alternatively, these proteins can interact with keratin intermediate filaments. Filaggrin undergoes further processing in the upper stratum corneum to release free amino acids that assist in water retention.
s in the gene
coding for filaggrin are strongly predisposed to a severe form of dry skin, ichthyosis vulgaris
, and/or eczema
.
Scientists hope to develop treatments for eczema through their newfound knowledge of filaggrin.
Truncation mutations R501X and 2284del4 are the most common mutations in the caucasian
population, with 7-10% of the caucasian population carrying at least one copy of these mutations.
It has been shown that almost 50% of all severe cases of eczema may have at least one mutated filaggrin gene.
R501X and 2284del4 are not generally found in non-caucasian individuals, though novel mutations (3321delA and S2554X) have been found in Japanese populations that yield similar effects.
Autoantibodies in rheumatoid arthritis
recognizing an epitope
of citrullinated peptides are cross-reactive with filaggrin.
The barrier defect seen in filaggrin null carriers also appears to lead to increased asthma susceptibility and exacerbations. Filaggrin deficiency is one of the top genome-wide genetic determinants of asthma, along with the variants found that regulate ORMDL3 expression.
The penetrance of filaggrin mutations may be increased by household exposure to cats.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that binds to keratin
Keratin
Keratin refers to a family of fibrous structural proteins. Keratin is the key of structural material making up the outer layer of human skin. It is also the key structural component of hair and nails...
fibers in epithelial cell
Epithelium
Epithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective...
s.
Profilaggrin
Filaggrin monomers are tandemly clustered into a large, 350kDa protein precursor known as profilaggrin. In the epidermis, these structures are present in the keratohyalin granules in cells of the stratum granulosumStratum granulosum
The stratum granulosum is a thin layer of cells in the epidermis. Keratinocytes migrating from the underlying stratum spinosum become known as granular cells in this layer...
. Profilaggrin undergoes proteolytic
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
processing to yield individual filaggrin monomers at the transition between the stratum granulosum
Stratum granulosum
The stratum granulosum is a thin layer of cells in the epidermis. Keratinocytes migrating from the underlying stratum spinosum become known as granular cells in this layer...
and the stratum corneum
Stratum corneum
The stratum corneum is the outermost layer of the epidermis, consisting of dead cells that lack nuclei and organelles. The purpose of the stratum corneum is to form a barrier to protect underlying tissue from infection, dehydration, chemicals and mechanical stress...
, which may be facilitated by calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
-dependant enzymes.
Function
Filaggrin is essential for the regulation of epidermal homeostasis. Within the stratum corneumStratum corneum
The stratum corneum is the outermost layer of the epidermis, consisting of dead cells that lack nuclei and organelles. The purpose of the stratum corneum is to form a barrier to protect underlying tissue from infection, dehydration, chemicals and mechanical stress...
, filaggrin monomers can become incorporated into the lipid envelope, which is responsible for the skin barrier function. Alternatively, these proteins can interact with keratin intermediate filaments. Filaggrin undergoes further processing in the upper stratum corneum to release free amino acids that assist in water retention.
Clinical significance
Individuals with truncation mutationMutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s in the gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
coding for filaggrin are strongly predisposed to a severe form of dry skin, ichthyosis vulgaris
Ichthyosis vulgaris
Ichthyosis vulgaris is a skin disorder causing dry, scaly skin. It is the most common form of ichthyosis, affecting around 1 in 250 people. For this reason it is known as common ichthyosis...
, and/or eczema
Eczema
Eczema is a form of dermatitis, or inflammation of the epidermis . In England, an estimated 5.7 million or about one in every nine people have been diagnosed with the disease by a clinician at some point in their lives.The term eczema is broadly applied to a range of persistent skin conditions...
.
Scientists hope to develop treatments for eczema through their newfound knowledge of filaggrin.
Truncation mutations R501X and 2284del4 are the most common mutations in the caucasian
Caucasian race
The term Caucasian race has been used to denote the general physical type of some or all of the populations of Europe, North Africa, the Horn of Africa, Western Asia , Central Asia and South Asia...
population, with 7-10% of the caucasian population carrying at least one copy of these mutations.
It has been shown that almost 50% of all severe cases of eczema may have at least one mutated filaggrin gene.
R501X and 2284del4 are not generally found in non-caucasian individuals, though novel mutations (3321delA and S2554X) have been found in Japanese populations that yield similar effects.
Autoantibodies in rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
recognizing an epitope
Epitope
An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The part of an antibody that recognizes the epitope is called a paratope...
of citrullinated peptides are cross-reactive with filaggrin.
The barrier defect seen in filaggrin null carriers also appears to lead to increased asthma susceptibility and exacerbations. Filaggrin deficiency is one of the top genome-wide genetic determinants of asthma, along with the variants found that regulate ORMDL3 expression.
The penetrance of filaggrin mutations may be increased by household exposure to cats.