In other species: taurine cattle , sheep

Categories: Integument (skin) phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 226700 (trait) , 226650 (trait) , 150292 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2002

Cross-species summary: Junctional epidermolysis bullosa, Herlitz-type is a severe subtype of junctional epidermolysis bullosa (JEB) characterized by blisters and extensive erosions, localized to the skin and mucous membranes. [ Orphanet:79404 ]

Species-specific name: Junctional epidermolysis bullosa

Species-specific symbol: JEB

Species-specific description: Several cases of junctional epidermolysis bullosa (JEB) were described for Belgian draft horse foals and similarity to a condition in humans was identified (Frame et al., 1988; Johnson et al. 1988; Kohn et al., 1989; Shapiro and McEwen, 1995). A likely causal variant was identified in the LAMC2 gene (Spirito et al., 2002). The same variant was later reported to cause JEB in the Trait Briton and the Trait Comtois draft horses in France (Milenkovic et al., 2003), and in an Italian draft horse (Cappelli et al., 2015). [IT thanks Margaret Higgins, working under the guidance of Professor Ernie Bailey, for contributions to this entry in April 2022]

Inheritance: A mare produced two affected foals when bred to two different stallions (Kohn et al., 1989). Similarity to a hereditary condition in people suggested a recessive, autosomal mode of inheritance. Histological studies suggested an absence of the LAMC2 gene product, making this a primary candidate gene for sequencing. After the variant in LAMC2 was identified a pedigree study involving 148 Belgian horses from the United States confirmed the autosomal recessive mode of inheritance (Spirito et al., 2002).

Molecular basis: By cloning and sequencing a very likely candidate gene (based on the disorder being associated with "the absent expression of the gamma2 chain of laminin 5"), Spirito et al. (2002) identified a likely causal mutation as a single bp duplication in the equine LAMC2 gene, namely "1368insC [which] results in a downstream premature termination codon and is predicted to cause absent expression of the laminin gamma2 polypeptide". The first reports of this disorder in French and later Italian draft horses involved the same mutation (published as 1368insC in LAMC2) as apparently causal (Milenkovic et al., 2003; Cappelli et al., 2015).

Clinical features: "Lesions can be present at birth or develop over a short period of time and are characterized by the development of vesicles and bullae that rapidly progress to erosions and ulcerations at sites of minor trauma such as the lips, the oral mucosa, and distal extremities and the coronary band, with resulting sloughing of the hoofs ... . Lesions can be secondarily affected or become pustules. Affected animals may die soon after birth due to inability to suckle.“ (Capelli et al. 2015)

Pathology: Spirito et al. (2002): "Electron microscopy examination revealed junctional blistering and abnormal hemidesmosomes (Johnson et al., 1988)"

Breeds: Belgian Draft (Horse) (VBO_0000915), Breton, France (Horse) (VBO_0010460), Cavallo Agricolo Italiano da Tiro Pesante Rapido, Italy (Horse) (VBO_0011580), Comtois (Horse) (VBO_0000936).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: