A frameshift mutation within LAMC2 is responsible for Herlitz type junctional epidermolysis bullosa (HJEB) in black headed mutton sheep.

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.

Epidermolysis bullosa in German black headed mutton sheep.

In three flocks, 13 pure- and 1 crossbred German black headed mutton lambs were ascertained which had clinical signs of epidermolysis bullosa (EB). The three farmers reported of further 20 affected lambs with similar signs in their flocks in the past lambing seasons. The affected lambs were progeny of six rams and 17 ewes. Two rams and six ewes with affected offspring from two farms were used for a breeding trial. In the course of these experimental matings, 21 lambs were born, six of which were affected by EB. All lambs born in this trial underwent clinical and haematological examination and all the affected lambs had to be euthanised due to severe and progressing clinical symptoms. Clinical examinations in 20 affected lambs revealed shedding of claw horn, erosions and ulcers of skin and mucous membranes. Histopathology showed subepidermal splitting and blistering with intact basal keratinocytes. These findings together with the premature death of affected lambs within the first two months of life made a Herlitz type of junctional EB most likely. The results of the test matings demonstrated the genetic transmission and indicated an autosomal recessive mode of inheritance for this lethal condition.