LAMA3 gene.....Location

Location…..

Cytogenetic Location      : 18q11.2

Molecular Location        : base pairs 21,269,561-21,535,029 on chromosome 18

The LAMA3 gene is located on the long (q) arm of chromosome 18 at position 11.2, precisely, the LAMA3 gene is located from base pair 21,269,561 to base pair 21,535,029 on chromosome 18.

LAMA3 gene.....Official Name

Official Name               :      Laminin, alpha 3

Official Symbol             :      LAMA3 

The LAMA3 gene is also known by other names…..

   @   BM600

   @   BM600-150kDa

   @   BM600 150kD subunit

   @   E170

   @   epiligrin

   @   epiligrin 170 kda subunit

   @   epiligrin alpha 3 subunit

   @   kalinin-165kDa

   @   kalinin 165kD subunit

   @   LAM5, alpha-3 subunit

   @   lama3a

   @   LAMA3_HUMAN

   @   laminin-5 alpha 3 chain

   @   laminin 5, alpha-3 subunit

   @   laminin A3

   @   laminin alpha 3

   @   laminin alpha 3 subunit

   @   LAMNA

   @   LOCS

   @   nicein-150kDa

   @   nicein 150kD subunit

The Genes....[JEB]

What genes are related to Junctional Epidermolysis Bullosa?

Junctional Epidermolysis Bullosa [JEB] is caused due to the mutations in the LAMA3, LAMB3, LAMC2 and COL17A1 genes. Mutations in each of these genes can cause Herlitz JEB or non-Herlitz JEB. LAMB3 gene mutations are the most common causing almost 70% of all cases of JEB.

Each of the LAMA3, LAMB3 and LAMC2 gene provides instructions for making one part (subunit) of a protein called ‘Laminin 332’. This protein plays an important role in strengthening and stabilizing the skin by helping the top layer of skin (the epidermis) to attach with the underlying layers. Mutations in any of the three ‘Laminin 332’ genes lead to the production of a defective or non-functional version of this protein. Without functional laminin 332, cells in the epidermis become fragile and easily damaged. Friction or other minor trauma can cause the skin layers to separate, causing the formation of blisters.

The COL17A1 gene provides instructions for making a protein which used to assemble type ‘XVII collagen’. Collagen provides structure and strength to connective tissues such as skin, tendons and ligaments throughout the body. Type XVII collagen helps the epidermis to attach with underlying layers of skin, making the skin strong and flexible. Mutations in the COL17A1 gene prevent the normal formation of collagen XVII — as a result, the skin become less resistant to friction which leads to the formation of blisters due to minor trauma. Most COL17A1 gene mutations cause non-Herlitz JEB, although a few individuals with mutations in this gene have had the more severe Herlitz JEB.

Prevalence....[JEB]

How common is Junctional Epidermolysis Bullosa [JEB]?

Both types of JEB are rare, affecting less than 1 per million people in the United States.

Genetics.....[JEB]

Junctional Epidermolysis Bullosa [JEB].....

Junctional epidermolysis bullosa (JEB) is one of the major forms of Epidermolysis Bullosa.

Junctional Epidermolysis Bullosa [JEB] can be classified into 2 main types: ‘Herlitz JEB’ and ‘non-Herlitz JEB’. Although the types differ in severity but their features overlap significantly—which is caused by mutations in the same genes.

Herlitz JEB is the more severe form of JEB. From birth or early infancy the baby has blistering over large regions of the body. Blistering also affects the mucous membranes such as the moist lining of the mouth and digestive tract which makes eating and swallowing difficult which in turn creates problems in digestion. As a result many affected children have chronic malnutrition and slow growth. The extensive blistering leads to scarring and the formation of red, bumpy patches called ‘granulation tissue’. Granulation tissue bleeds easily and profusely, making affected infants susceptible to serious infections and loss of necessary proteins, minerals, and fluids. Additionally, a build-up of granulation tissue in the airway can lead to a weak, hoarse cry and difficulty breathing. Other complications of Herlitz JEB may include fusion of the fingers and toes, abnormalities of the fingernails and toenails, joint deformities (contractures) that restrict movement and hair loss (alopecia). Because the signs and symptoms of Herlitz JEB are so severe, infants with this condition usually do not survive beyond the first year of life.

Exuberant granulation tissue arising on the nape of the neck of a child with Herlitz JEB.

Fine Orphanet Journal of Rare Diseases 2010 5:12 

The milder form of JEB is called non-Herlitz JEB. The blistering associated with non-Herlitz JEB usually limited to the hands, feet, knees and elbows which often improves after the newborn period. Other characteristic features of non-Herlitz JEB include alopecia, malformed fingernails and toenails and irregular tooth enamel. Most affected individuals do not have extensive scarring or granulation tissue formation, so breathing difficulties and other severe complications are rare. Non-Herlitz JEB is typically associated with a normal lifespan.

A Rare kind of EBS

In rare cases of Epidermolysis Bullosa Simplex (EBS), no KRT5 or KRT14 gene mutations have been identified. Mutations in another gene — ‘PLEC’ — have been associated with the uncommon ‘Ogna type’ of the condition. The PLEC gene provides instructions for making a protein called ‘Plectin’ which helps the ‘Epidermis’ to attach with the underlying layers of skin.

Research is going in the search of PLEC gene mutations in people with EBS. Researchers are also working on how these mutations lead to the major features of Epidermolysis Bullosa Simplex [EBS].

How Epidermolysis Bullosa Simplex [EBS] is caused due to mutation in the KRT14 gene?

EBS is caused by mutations in the KRT14 gene.

More than 60 mutations in the KRT14 gene have been identified in people with EBS. Most of the mutation alters single protein building blocks — amino acids — used to make ‘keratin 14’.

The most severe form of EBS — the Dowling-Meara type —  usually results from mutations in regions of the KRT14 gene which are essential for the normal assembly of keratin intermediate filaments.

Milder forms of the disorder — the Weber-Cockayne and Koebner types — are often caused by mutations in less critical regions.

The mutations in the KRT14 gene change the structure and function of ‘keratin 14’, preventing it from working effectively with ‘keratin 5’ and interfering with the assembly of the keratin intermediate filament network. A disruption in this network makes ‘keratinocytes’ fragile and prone to rupture. Minor trauma to the skin such as rubbing or scratching can cause these cells to break down, resulting in the formation of painful, fluid-filled blisters.

KRT14 Gene : Location

Location

Cytogenetic Location        : 17q12-q21

Molecular Location       : Base pairs 39,738,530 — 39,743,146 on chromosome 17.

The KRT14 gene is located on the long (q) arm of chromosome 17 at position 12 and 21, precisely, from base pair 39,738,530 to base pair 39,743,146.

KRT14 Gene : Function

Function of the KRT14 gene...

The KRT14 gene provides instructions for making a protein called ‘keratin 14’.

As we already discussed in KRT5 gene ‘Keratins’ are a group of tough, fibrous proteins that form the structural framework of certain cells, particularly cells that make up the skin, hair, and nails. Keratin 14 is specifically produced in cells called keratinocytes in the outer layer of the skin (the epidermis).

Keratin 14 partners with a similar protein, ‘keratin 5’, to form molecules called keratin intermediate filaments. These filaments assemble into strong networks which help keratinocytes to attach together and anchor the epidermis to underlying layers of skin. The network of keratin intermediate filaments provides strength and resiliency to the skin and protects it from being damaged by friction and other everyday physical stresses.

Researchers believe that keratin 14 may also play a role in the formation of sweat glands and the development of patterned ridges on the skin of the hands and feet. These ridges, called ‘dermatoglyphs’, are the basis for each person's unique fingerprints.

KRT14 Gene : Gene Family

The Gene Family…

Like KRT5, the KRT14 gene belongs to the same family of genes called KRT (keratins).

KRT14 Gene : The name...

The official name of the KRT14 Gene…

Official Name  : ‘keratin 14’

Official Symbol : KRT14 is the gene's official symbol

Other Names used for the KRT14 gene or gene products…

@ CK14

@ cytokeratin 14

@ EBS3

@ EBS4

@ K1C14_HUMAN

@ K14

@ Keratin-14

@ Keratin 14

@ keratin, type I cytoskeletal 14

How Epidermolysis Bullosa Simplex [EBS] cause?

EBS is caused by mutations in the KRT5 gene.

More than 100 mutations in the KRT5 gene have been identified in people suffering with EBS. Most of the mutation alters single protein building blocks — amino acids — used to make ‘keratin 5’.

The most severe form of EBS — the Dowling-Meara type— usually caused by the mutations in the regions of keratin 5 gene which are essential for the normal assembly of keratin intermediate filaments.

Milder forms of the disorder — the Weber-Cockayne and Koebner types — are often caused by mutations in less critical regions of the protein.

Epidermis Bullosa Simplex with mottled pigmentation typically results from a particular KRT5 mutation. This mutation replaces the amino acid ‘proline’ with the amino acid ‘leucine’ at protein position 25 (expressed as Pro25Leu or P25L).

The mutations in the gene KRT5 change the structure and function of ‘keratin 5’, preventing it from working effectively with keratin 14 and interfering with the assembly of the keratin intermediate filament network. A disruption in this network makes keratinocytes fragile and prone to rupture. Minor trauma to the skin such as rubbing or scratching can cause these cells to break down, resulting the formation of painful, fluid-filled blisters.

KRT5 Gene : Location

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Location

Cytogenetic Location     : 12q13.13

Molecular Location   : Base pairs 52,908,358 — 52,914,242 on chromosome 12.

The KRT5 gene is located on the long (q) arm of chromosome 12 at position 13.13, precisely, from base pair 52,908,358 to base pair 52,914,242.