Animal models for skin blistering conditions: absence of laminin 5 causes hereditary junctional mechanobullous disease in the Belgian horse.
Abstract: Recent achievements in the genetic correction of keratinocytes isolated from patients with junctional epidermolysis bullosa have paved the way to a gene therapy approach for the disease. Because gene therapy protocols require preclinical validation in animals, we have characterized spontaneous animal models of junctional epidermolysis bullosa. In this study we have elucidated the genetic basis of the hereditary junctional mechanobullous disease in the Belgian horse, a condition characterized by blistering of the skin and mouth epithelia, and exungulation (loss of the hoof). Immunofluorescence analysis associated the condition to the absent expression of the gamma2 chain of laminin 5 and designated Lamc2 as the candidate gene. Comparative analysis of the nucleotide sequence of the full-length gamma2 cDNA isolated by reverse transcription polymerase chain reaction amplification of total RNA purified from the epithelium of a junctional epidermolysis bullosa foal and a healthy control disclosed a homozygous basepair insertion (1368insC) in the affected animal. Mutation 1368insC results in a downstream premature termination codon and is predicted to cause absent expression of the laminin gamma2 polypeptide. Our results also show that: (i) the horse junctional epidermolysis bullosa genetically corresponds to the severe Herlitz form of junctional epidermolysis bullosa in man; (ii) the amino acid sequence and structure of the horse laminin gamma2 chain are virtually identical to the human counterpart; (iii) the moderate eruption of skin blisters in the affected animals with respect to the human Herlitz junctional epidermolysis bullosa patients correlates with the protection provided by hair. Our observations suggest that the affected foals are a convenient source of epithelial cells from tissues that cannot be obtained from human junctional epidermolysis bullosa patients, and imply that hairless strains of animals with recessive skin disorders would be the best models for in vivo gene therapy approaches to skin blistering diseases.
Publication Date: 2002-09-17 PubMed ID: 12230513DOI: 10.1046/j.1523-1747.2002.01852.xGoogle Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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The research focuses on an inherited disease in Belgian horses that causes skin blistering, which is similar to a severe human skin condition, junctional epidermolysis bullosa. Researchers found that this disease in horses is genetically linked to the absence of a certain gene (Lamc2) and propose that the affected horses could provide valuable insights for developing gene therapy approaches for similar human skin conditions.
Objective and Background of the Study
- The research aims at characterizing the genetic basis of a hereditary skin blistering disease found in Belgian horses, which shows similarities to the severe Herlitz form of junctional epidermolysis bullosa in humans.
- Junctional epidermolysis bullosa is a disease that causes skin blistering and exungulation (loss of the hoof in horses or nails in humans).
- With advancements in genetic correction of skin cells (keratinocytes) obtained from human patients with junctional epidermolysis bullosa, researchers are now looking at gene therapy approaches to treat this disease.
- Before implementing gene therapy in humans, the procedures need to be validated in animal models.
Research Methodology
- Using immunofluorescence analysis, the study associated the blistering condition in Belgian horses to the absent expression of gamma2 chain of a protein called laminin 5.
- To further understand the genetic foundations, the researchers isolated and compared the nucleotide sequence of the full-length gamma2 cDNA from an affected horse (a foal with junctional epidermolysis bullosa) and a healthy control.
- The analysis revealed a homozygous base pair insertion (1368insC) in the affected horse. This mutation is predicted to disrupt the expression of laminin gamma2 polypeptide.
Findings and Conclusion
- The study confirms that the horse junctional epidermolysis bullosa corresponds genetically to the severe Herlitz form of the condition in humans.
- It was found that the structure and amino acid sequence of the horse laminin gamma2 chain are almost identical to the human counterpart.
- The reduced severity of skin blisters in horses compared to humans suffering from the Herlitz form of the disease is likely due to the protection provided by horse hair.
- The findings suggest that the affected foals could serve as a significant source of epithelial cells for research as obtaining such tissues from human patients is often difficult.
- The study also implies that hairless strains of animals with recessive skin disorders may serve as optimal models for in vivo gene therapy approaches to skin blistering diseases.
Cite This Article
APA
Spirito F, Charlesworth A, Linder K, Ortonne JP, Baird J, Meneguzzi G.
(2002).
Animal models for skin blistering conditions: absence of laminin 5 causes hereditary junctional mechanobullous disease in the Belgian horse.
J Invest Dermatol, 119(3), 684-691.
https://doi.org/10.1046/j.1523-1747.2002.01852.x Publication
Researcher Affiliations
- INSERM U385, Faculté de Médecine, Nice, France.
MeSH Terms
- Animals
- Blister / genetics
- Blister / physiopathology
- Cell Adhesion Molecules / genetics
- DNA, Complementary
- Disease Models, Animal
- Epidermolysis Bullosa, Junctional / genetics
- Epidermolysis Bullosa, Junctional / physiopathology
- Epithelium / pathology
- Genotype
- Horses
- Humans
- Joints / pathology
- Laminin / genetics
- Molecular Sequence Data
- Pedigree
- Point Mutation
- Sequence Homology, Amino Acid
Citations
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