Article

Inherited junctional epidermolysis bullosa in the German Pointer: establishment of a large animal model.

INSERM U634, Faculty of Medicine, University Hospital, Nice Cedex, France.
Journal of Investigative Dermatology (impact factor: 6.31). 04/2005; 124(3):530-5. DOI:10.1111/j.0022-202X.2004.23584.x pp.530-5
Source: PubMed

ABSTRACT Junctional epidermolysis bullosa (JEB) is a genodermatosis suitable for gene therapy because conventional treatments are ineffective. Here, we elucidate the genetic basis of mild JEB in a breed of dogs that display all the clinical traits observed in JEB patients. The condition is associated with reduced expression of laminin 5 caused by a homozygous insertion (4818+207ins6.5 kb) of repetitive satellite DNA within intron 35 of the gene (lama3) for the laminin alpha3 chain. The intronic mutation interferes with maturation of the alpha3 pre-messenger RNA resulting in the coexpression of a transcript with a 227 nucleotide insertion and a wild-type mRNA that encodes scant amounts of the alpha3 polypeptide. Our results show that the amino acid sequence and structure of the canine and human alpha3 chain are highly conserved and that the reduced expression of laminin 5 affects the adhesion and clonogenic potential of the JEB keratinocytes. These JEB dogs provide the opportunity to perform gene delivery in a naturally occurring genodermatosis and to evaluate host tolerance to recombinant laminin 5.

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    Article: A frameshift mutation within LAMC2 is responsible for Herlitz type junctional epidermolysis bullosa (HJEB) in black headed mutton sheep.
    Stefanie Mömke, Andrea Kerkmann, Anne Wöhlke, Miriam Ostmeier, Marion Hewicker-Trautwein, Martin Ganter, James Kijas, Ottmar Distl
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    ABSTRACT: Junctional epidermolysis bullosa (JEB) is a hereditary mechanobullous skin disease in humans and animals. A Herlitz type JEB was identified in German Black Headed Mutton (BHM) sheep and affected lambs were reproduced in a breeding trial. Affected lambs showed skin and mucous membranes blistering and all affected lambs died within the first weeks of life. The pedigree data were consistent with a monogenic autosomal recessive inheritance. Immunofluorescence showed a reduced expression of laminin 5 protein which consists of 3 subunits encoded by the genes LAMA3, LAMB3 and LAMC2. We screened these genes for polymorphisms. Linkage and genome-wide association analyses identified LAMC2 as the most likely candidate for HJEB. A two base pair deletion within exon 18 of the LAMC2 gene (FM872310:c.2746delCA) causes a frameshift mutation resulting in a premature stop codon (p.A928*) 13 triplets downstream of this mutation and in addition, introduces an alternative splicing of exon 18 LAMC2. This deletion showed a perfect co-segregation with HJEB in all 740 analysed BHM sheep. Identification of the LAMC2 deletion means an animal model for HJEB is now available to develop therapeutic approaches of relevance to the human form of this disease.
    PLoS ONE 01/2011; 6(5):e18943. · 4.09 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

227 nucleotide insertion
 
alpha3 polypeptide
 
alpha3 pre-messenger RNA
 
amino acid sequence
 
clonogenic potential
 
coexpression
 
encodes scant amounts
 
gene delivery
 
genetic basis
 
human alpha3 chain
 
intron 35
 
intronic mutation interferes
 
JEB keratinocytes
 
Junctional epidermolysis bullosa
 
laminin alpha3 chain
 
mild JEB
 
occurring genodermatosis
 
recombinant laminin 5
 
reduced expression
 
repetitive satellite DNA
 

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