Mutations In The A6 And B4 Integrin Genes Biology Essay

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Epidermolysis bullosa is a hereditary disorder, caused by mutations in 10 different cutaneous basement membrane zone genes. These defective genes include the ones for type VII collagen (COL7A1), mutations in the Laminin genes LAMA3, LAMB3 and LAMC2 these cause a lethal Herlitz variant of junctional Epidermolysis bullosa; mutations in the a 6 and b4 integrin genes in a distinct hemidesmosomal variant of EB with congenital pyloric atresia; and mutations in the plectin gene PLEC1. (Vark, R., et al. 2006) A form of EB that leads to muscular dystrophy has also been linked to mutations in the PLEC1 generproteins. (Dang, M., et al, 1998) EB leads to extreme blistering and ulcers due to the fragility of the skin and mucus membranes. This could be caused by the slightest trauma or friction to skin. In more extreme cases of EB, there could be involvement of skin, teeth, the gastrointestinal, urinary tract and pulmonary epithelia. EB affects approximately 1 in 17, 000 live births with an estimated half million cases reported worldwide. The inheritance can either be automomal dominant or autosomal recessive. Occurrence of EB is not dependant on race or gender. (Yancey, K and Hintner, H., 2010)

There are currently four subtypes of EB that have been identified. Firstly Epidermolysis bullosa simplex, Junctional Epidermolysis bullosa, Dystrophic Epidermolysis bullosa and a fourth autoimmune form with manifests its self during the fourth or fifth decade of life, caused by the production of Immunoglobulin (Ig) G autoantibodies to collagen VII (Hossein, C., et al., 2000) Advances in molecular genetic analysis have paved the way for identification of specific mutations. Different mutations that occurred have been found to be deletion or insertions of genes, nonsense, nonsynonymous, splicing frameshift and inframe of genes coding for the adhesion molecules of the epidermal basement membrane. (Hovnanian A, et al., 1992)

Epidermolysis bullosa (EB) simplex.

In the majority of EB simplex have been found to be autosomal dominant, although the mode of transmission is recessive in some subtypes, such as autosomal recessive EB simplex, lethal acantholytic EB simplex, plakophilin deficiency, EB simplex with muscular dystrophy, and EB simplex with pyloric atresia. (Schara, U, et at., 2004.) The Defective genes identified causing EB simplex are; 1. KRT5 encoding for Keratin 5, and KRT14 encoding for Keratin 14; these two keratin genes code for intermediate filament cytoskeleton proteins in basal keratinocytes, maintaining rigidness of the epidermis against frictional forces. Recently, a number of additional functions of there intermediate filaments have been discovered. These include regulation of key signalling pathways controlling cell survival, cell growth, and vectorial processes associated with protein targeting, vesicle transport, and cell adhesion this causes Blisters with redness and inflammation generally caused by friction and aggravated by sweating and excessive heat. (Fassihi H, et al., 2006) This type of EB simplex is localised to the hands and feet. 2. DSP encoding for Desmoplakin, this defective gene leads to an onset of weak adhesion of epithelial and muscle adhesion. Due to this weakness a patient has skin is very fragile, hair is absent on the entire body, nails fall of on toes and fingers, and there some involvement with neonatal teeth. Skin fragility is so severe, that slight rubbing of the skin causes skin to peel this is known as a Nikolsky sign. This form of EB gives rise to erosive wounds rather than blisters and vesicles. (Jonkman MF, et al., 2005) 3. PKP1 encoding for Plakophilin 1, this defective gene causes defects in the structure of desmosomes. This type of EB usually manifests at birth, the new born is presented with fragile skin, blistering, and general inflammation and redness. These are accompanied by abnormal or absent hair growth, thickening of nails, palms and soles of feet. This may also involve the oesophagus, mouth and throat. (Uitto J, and Richard G., 2005) Other gene include PLEC1 encoding for Plectin, and ITGA6, ITGB4 encoding for Integrin, a6b4.

Junctional Epidermolysis bullosa (JEB)

Junctional EB is characterized by separation at the lamina lucida of the epidermal basement membrane zone (BMZ). This sub unit of EB come about by autosomal recessive inheritance. The condition is usually presented at birth, with localised or generalised lesions, except in the case of late onset Junctional EB. The mucous membranes, in particular the oral, gastrointestinal, ocular, and respiratory membranes, are affected mainly in Junctional EB. Mutations in the three genes, LAMA3, LAMB3, and LAMC2 that encode, a3, b3, and g2 olypeptide subunits of laminin 332. Premature termination codons in the alleles of any of these three genes result s in the absence of laminin 332 in the skin of the affected individuals. (Mavilio F, et al., 2006.)

Mutations in the COL17A1 encoding for Collagen XVII has also been a underline cause of Junctional EB, this can either be a homozygous or heterozygous mutations leading to premature termination codons resulting in the lack of collagen XVII in the skin, insufficient for the formation of functional Hemidesmosome cytoskeleton and hemidesmosome anchoring filament interactions; missense mutations in one or both of the alleles associated mainly with blistering on extremities and mild skin atrophy. (Fine JD, et al., 2008) COL17A1 mutations are milder and don't generally affect the nails of the fingers and toes but severely affects the skin on the buttocks, blistering and ulceration of the skin mainly on the face and neck, poor development or lack of dental enamel, as well as adhesion of the eyelid this can lead to blindness and conjunctival tumour. There have been cased were patients develop respiratory tract abnormalities or anaemia as a result of bleeding from wounds (Pfendner EG, et al., 2007). Dideoxynucleotide sequencing has revealed that at nucleotide position 1903 of the LAMB3 in cDNA, there is a C to T transition that causes a premature termination codon in maternal heterozygous mutation. Paternal; COL17A1 mutation, occurs on nucleotide position 2669, where there is a T to G transversion in exon 37. (Floeth, M and Tuderma, LB., 1999)

Mutational defects have been identified, as well on, ITGA6, ITGB4 encoding Integrin, a6b4 The inherited G to A transition at the last base of exon 7 converts a negatively charged glutamic acid residue into a positively charged lysine. This substitution takes place within the N-terminal globular domain of the short arm of the LM-332 β3 chain, which has been theorised highly important in the association of LM-332 with other structural proteins of the BMZ, including laminin-311 due to this shift in polarity the protein-protein interactions of LM-332 leads to reduced epidermal-dermal adhesion. (Anna M.G, et al., 2007)

Dystrophic Epidermolysis bullosa.

Dystrophic EB is caused by mutations of COL17A1 that affect collagen VII, the protein that forms the anchoring fibrils of the epidermal basement membrane. This can be inherited either autosomal dominant or autosomal recessive. The recessive forms of the type are less common and generally less severe. Mutations in dominant Dystrophic Epidermolysis bullosa usually involve glycine substitutions within the triple helix of COL7A1 although other missense variants, internal deletions or splice-site alterations maybe underling causes in some cases. In the case of dominant Dystrophic Epidermolysis bullosa the allelic variants include nonsense, splice site, internal deletions or insertions, "silent" glycine substitutions within the triple helix, two variants were identified in the COL7A1 gene, they were a single G to C base substitution at nucleotide 6127 (or DNA nucleotide 23592) a nucleotide change of G to A at position 6127. (Fine JD, et al., 2008) and non-glycine missense variants within the triple helix or non-collagenous NC-2 domain Dystrophic Epidermolysis bullosa is generally due to nonsense, frame-shift or splice-site variants on both alleles leading to premature termination codons which result in short polypeptides that are unable to develop into functional anchoring filaments.( Anna M.G, et al., 2007)

Recessive Dystrophic Epidermolysis bullosa results from a G to A transition in exon 112 creating an AGT codon from a GGT and results in the substitution of a serine for a glycine at position 2775 of polypeptide. (REF) the blisters usually appear on the shins and feet, and to a lesser degree on the hands, In dominant dystrophic EB, blisters appear only on the hands and feet. In the generalized dominant form of dystrophic EB hypopigmentated papules can appear on the torso. In the generalised forms of the disease, blistering tends to become more localised as the patient gets older. A rare variant of Dominant EB (dystrophic epidermolysis pruriginosa) is characterized by itching. (Pfendner EG, et al., 2007.) Certain type of dystrophic EB can only the nails and does not involve blistering of the skin.

This form EB is manifested and shows symptoms from birth, but can also appear during infancy. The recessive subtypes also range from mild and localized forms these are pretibial recessive dystrophic EB, inverse recessive dystrophic EB, and recessive dystrophic EB centripetalis to severe and generalised disease certain severe generalised recessive dystrophic EB and recessive dystrophic EB, and other generalised other. The recessive inverse form, which gives rise to localized blistering characterized by skin rubbing together (adhesion), lumbosacral, axial or on the extremities of the body. This subtype carries a high risk of narrowing the external ear canal. (Anna M.G, et al., 2007)


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