Mutation in COL7A1 cause Dystrophic Epidermolysis Bullosa

More than 400 mutations in the COL7A1 gene cause Dystrophic Epidermolysis Bullosa [DEB]. These mutations alter the structure/disrupt the production of ‘type VII collagen’, which impairs the ability of anchoring fibrils to connect the epidermis to the dermis. When type VII collagen is abnormal or missing, anchoring fibrils cannot able to form properly. As a result, friction or other minor trauma can cause the two skin layers to separate. This separation leads to the formation of blisters, which results in extensive scarring as they heal.

The autosomal recessive types of dystrophic epidermolysis bullosa (RDEB) result from mutations in both copies of the COL7A1 gene in each cell. 

The most severe, classic form of this disorder is known as the ‘Hallopeau-Siemens type (RDEB-HS)’. Most of the COL7A1 mutations responsible for RDEB-HS significantly reduce or eliminate the production of type VII collagen. As a result, few or no anchoring fibrils are present to connect the epidermis with the dermis. This lack of anchoring fibrils causes the severe signs and symptoms of RDEB-HS. 

A to some extent less severe form of autosomal recessive dystrophic epidermolysis bullosa, known as the ‘non-Hallopeau-Siemens type (Non-HS RDEB)’, is caused by other types of mutations. These genetic changes allow a small amount of normal or partially functional type VII collagen to be produced.

Source: www.ghr.nlm.nih.gov

COL7A1 gene ……….. Function

The COL7A1 gene provides instructions for making proteins for assembling type VII collagen. Collagens are a family of proteins that strengthen and support connective tissues such as skin, bone, tendons, and ligaments, throughout the body. In particular, type VII collagen plays an essential role in strengthening and stabilizing the skin.

The proteins produced from the COL7A1 gene — pro-α1 (VII) chains — are the components of type VII collagen. 3 pro-α1 (VII) chains twist together to form a triple-stranded, rope like molecule known as a ‘procollagen’. Procollagen molecules are secreted by the cell and processed by enzymes to remove extra protein segments from the ends. Once these molecules are processed, they arrange themselves into long, thin bundles of mature type VII collagen.

Type VII collagen is the major component of structures in the skin — the anchoring fibrils.

As we already discuss earlier in EB disease ‘anchoring fibrils’ are found in a region known as the Epidermal Basement Membrane Zone — which is a two-layer membrane located between the top layer of skin — the epidermis and an underlying layer — the dermis. Anchoring fibrils hold the two layers of skin together by connecting the epidermal basement membrane to the dermis.

Source: www.ghr.nlm.nih.gov

COL7A1 gene ……… Location

Cytogenetic Location :   3p21.1

Molecular Location   :    base pairs (bp) 48,601,505 ~ bp 48,632,592 on chromosome 3.

The COL7A1 gene is located on the short (p) arm of chromosome 3 at position 21.1, more precisely, from bp 48,601,505 ~ bp 48,632,592.

Source: www.ghr.nlm.nih.gov

COL7A1 gene…..Official Name

Official Name     : Collagen, type VII, alpha 1

Official Symbol   : COL7A1 

The COL7A1 gene is also known by other names...........

 @   alpha 1 type VII collagen

 @   CO7A1_HUMAN

 @   collagen, type VII, alpha 1

 @   collagen VII, alpha-1 polypeptide

 @   EBD1

 @   EBDCT

 @   EBR1

 @   LC collagen

 @   long chain collagen

The Genes……

Mutations in the COL7A1 gene cause all 3 major forms of Dystrophic Epidermolysis Bullosa [DEB]. This gene provides instructions for making a protein that is used to assemble ‘type VII collagen’. Collagens are molecules that give structure and strength to connective tissues such as skin, tendons and ligaments throughout the body. Type VII collagen plays an important role in strengthening and stabilizing the skin. It is the main component of 'Anchoring fibrils' —which anchor the top layer of skin—Epidermis to underlying Dermis.

COL7A1 mutations alter the structure or disrupt the production of ‘type VII collagen’ which impairs its ability to help connect the epidermis to dermis. When type VII collagen is abnormal or missing, friction or other minor trauma cause the two skin layers to separate. This separation leads to the formation of blisters which can cause extensive scarring as they heal.

Researchers are working to determine how abnormalities of type VII collagen also underlie the increased risk of skin cancer seen in the severe form of Dystrophic Epidermolysis Bullosa [DEB].

Source: www.ghr.nlm.nih.gov

Prevalence....

The incidence of all types of Dystrophic Epidermolysis Bullosa [DEB] is estimated to be 6.5 per million newborns in the United States. The severe autosomal recessive forms of this disorder affect less than 1 per million newborns.

Dystrophic Epidermolysis Bullosa [DEB]

Dystrophic Epidermolysis Bullosa [DEB] is one of the major forms of Epidermolysis Bullosa [EB]. The signs and symptoms of this condition vary widely among affected individuals. In mild cases, blistering may primarily affect the hands, feet, knees and elbows. Severe cases of this condition involve widespread blistering that can lead to vision loss, disfigurement and other serious medical problems.

Researchers classify Dystrophic Epidermolysis Bullosa [DEB] into 3 major types. Although the types differ in severity, their features overlap significantly and they are caused by mutations in the same gene.

Autosomal Recessive Dystrophic Epidermolysis Bullosa —‘Hallopeau-Siemens type (RDEB-HS)’ is the most severe, classic form of DEB. Affected infants are typically born with widespread blistering and areas of missing skin, often caused by trauma during birth. Most often, blisters are present over the whole body and affect mucous membranes such as the moist lining of the mouth and digestive tract. As the blisters heal, they result in severe scarring. Scarring in the mouth and esophagus can make it difficult to chew and swallow food, leading to chronic malnutrition and slow growth. Additional complications of progressive scarring can include fusion of the fingers and toes, loss of fingernails and toenails, joint deformities (contractures) that restrict movement and eye inflammation leading to vision loss. Additionally, young adults with the classic form of DEB have a very high risk of developing a form of skin cancer called ‘Squamous Cell Carcinoma’, which tends to be unusually aggressive and is often life-threatening.

The 2^nd type of Autosomal Recessive Dystrophic Epidermolysis Bullosa is known as the ‘non-Hallopeau-Siemens type (non-HS RDEB)’. This form of the condition is somewhat less severe than the classic type and includes a range of subtypes. Blistering is limited to the hands, feet, knees, and elbows in mild cases, but may be widespread in more severe cases. Affected people often have malformed fingernails and toenails. Non-HS RDEB involves scarring in the areas where blisters occur but this form of the condition does not cause the severe scarring characteristic of the classic type.

The 3^rd major type of DEB is known as the ‘Autosomal Dominant Type (DDEB)’. The signs and symptoms of this condition tend to be milder than those of the autosomal recessive forms, with blistering often limited to the hands, feet, knees, and elbows. The blisters heal with scarring but it is less severe. Most affected people have malformed fingernails and toenails and the nails may be lost over time. In the mildest cases abnormal nails are the only sign of the condition.

Source: www.ghr.nlm.nih.gov

LAMC2 gene cause JEB

More than 30 mutations in the LAMC2 gene have been identified in people with Junctional Epidermolysis Bullosa (JEB). The more severe form of the disease — ‘Herlitz JEB’ — results from mutations that severely disrupt the production of functional ‘laminin 332’. Most of these mutations lead to a premature stop signal in the instructions for making the gamma (g) subunit of laminin 332, which prevents the assembly of this protein. Without laminin 332, the epidermis is weakly connected to the underlying layers of skin. Friction even minor trauma (such as rubbing or scratching) can cause the skin layers to separate, leading to the formation of blisters. Infants with Herlitz JEB develop widespread blistering that causes life-threatening complications.

Other LAMC2 gene mutations cause the milder form of JEB —  ‘non-Herlitz JEB’. Some of these mutations alter single protein building blocks (amino acids) in the gamma (g) subunit of laminin 332. Others add or delete a small number of amino acids in the gamma (g) subunit or change the way the gene's instructions are used to make the subunit. The genetic changes responsible for non-Herlitz JEB usually lead to the production of a laminin 332 protein that retains some of its function. Affected individuals experience blistering, but it may be limited to the hands, feet, knees, and elbows and often improves after the newborn period.

Source: www.ghr.nlm.nih.gov

LAMC2 gene…..Function

Like LAMA3 & LAMB3, LAMC2 gene also provides instructions for making subunit of the protein — ‘laminin 332’ 

LAMC2 gene ….. Location

Cytogenetic Location    :   1q25-q31

Molecular Location    :   base pairs 183,155,173 - 183,214,261 on chromosome 1

The LAMC2 gene is located on the long (q) arm of chromosome 1 between positions 25 and 31, precisely from base pair (bp) 183,155,173 - bp 183,214,261.

LAMC2 gene….. Official Name

Official Name        :        laminin, gamma 2

Official Symbol      :        LAMC2 

The LAMC2 gene is also known by other names —

 @   B2T

 @   BM600

 @   BM600-100kDa

 @   cell-scattering factor (140kDa)

 @   CSF

 @   EBR2

 @   EBR2A

 @   kalinin-105kDa

 @   ladsin (140kDa)

 @   LAM5, gamma-2 subunit

 @   LAMB2T

 @   LAMC2_HUMAN

 @   laminin, nicein, beta-2

 @   LAMNB2

 @   MGC138491

 @   MGC141938

 @   nicein (100kDa)

 @   nicein-100kDa

LAMB3 gene cause JEB

How LAMB3 gene cause Junctional Epidermolysis Bullosa?

Mutation in LAMB3 gene causes Junctional Epidermolysis Bullosa [JEB]. 

More than 80 mutations in the LAMB3 gene have been identified in people with JEB. The more severe form of the disease, known as ‘Herlitz JEB’, usually results from mutations that severely disrupt the production of functional ‘laminin 332’. Most of these mutations lead to a premature stop signal in the instructions for making the beta subunit of laminin 332 which prevents the assembly of this protein. Without laminin 332, the epidermis is weakly connected to the underlying layers of skin. Friction or other minor trauma (such as rubbing or scratching) can cause the skin layers to separate, leading to the formation of blisters. Infants with Herlitz JEB develop widespread blistering that causes life-threatening complications.

Other LAMB3 gene mutations cause the milder form of JEB — ‘non-Herlitz JEB’. Some of these mutations alter single protein building blocks (amino acids) in the beta subunit of laminin 332. Others add or delete a small number of amino acids in the beta (β) subunit or change the gene's instructions to make the subunit. The genetic changes responsible for non-Herlitz JEB usually lead to the production of a defective laminin 332 protein. Affected individuals experience blistering but it may be limited to the hands, feet, knees, and elbows and often improves after the newborn period.

Source: www.ghr.nlm.nih.gov 

LAMB3 gene…..Function

Like LAMA3, LAMB3 gene also provides instructions for making one part (subunit) of a protein called ‘laminin 332’ (formerly known as laminin 5). As we discuss earlier ‘laminin 332’ is made up of three subunits — alpha (α), beta (β) and gamma (g). The LAMB3 gene carries instructions for the beta (β) subunit the alpha (α) and gamma (g) subunits are produced from other genes.

Source: www.ghr.nlm.nih.gov 

LAMB3 gene…..Location

Cytogenetic Location      :      1q32

Molecular Location         :      base pairs 209,788,214 to 209,825,819 on chromosome 1

The LAMB3 gene is located on the long (q) arm of chromosome 1 at position 32, precisely, the LAMB3 gene is located from base pair 209,788,214 to base pair 209,825,819 on chromosome 1.

LAMB3 gene…..Official Name

Official Name               :      Laminin, beta 3

Official Symbol             :      LAMB3

The LAMB3 gene is also known by other names…..

 @   BM600-125KDA

 @   FLJ99565

 @   kalinin-140kDa

 @   kalinin B1 chain

 @   LAM5, beta-3 subunit

 @   LAMB3_HUMAN

 @   laminin 5, beta-3 subunit

 @   laminin B1k chain

 @   laminin B3

 @   laminin, beta-3

 @   laminin, beta 3 precursor

 @   laminin S B3 chain

 @   LAMNB1

 @   nicein-125kDa

LAMA3 gene cause JEB

How LAMA3 gene cause Junctional Epidermolysis Bullosa?

Mutation in LAMA3 gene causes Junctional Epidermolysis Bullosa [JEB]. More than 30 mutations in the LAMA3 gene have been identified in people with junctional epidermolysis bullosa (JEB). The more severe form of the disease, known as ‘Herlitz JEB’, usually results from mutations which severely disrupt the production of functional ‘laminin 332’. Most of these mutations lead to a premature stop signal in the instructions for making the alpha (α) subunit of laminin 332, which prevents the assembly of this protein. Without laminin 332 the epidermis is weakly connected to the underlying layers of skin. Friction or any minor trauma (such as rubbing or scratching) can cause the skin layers to separate, leading to the formation of blisters. Infants with Herlitz JEB develop widespread blistering that causes life-threatening complications.

Other LAMA3 gene mutations cause the milder form of junctional epidermolysis bullosa, ‘non-Herlitz JEB’. Some of these mutations alter single protein building blocks (amino acids) in the alpha (α) subunit of laminin 332. Others add or delete a small number of amino acids in the alpha (α) subunit or change the way the gene's instructions are used to make the subunit. The genetic changes responsible for non-Herlitz JEB usually lead to the production of a laminin 332 protein which retains some of its function. Affected individuals experience blistering, but it may be limited to the hands, feet, knees, and elbows and often improves after the newborn period.

Source: www.ghr.nlm.nih.gov