ITGA6 homozygous splice-site mutation causes junctional epidermolysis bullosa in Charolais cattle
Abstract
Junctional epidermolysis bullosa (JEB), characterized by mechanically induced blisters of the skin and mucous membranes, is one of the most painful and life threatening recessive genetic disorders described in humans and other animal species. Congenital skin fragility resembling JEB was recently reported in three Charolais calves born in two distinct herds from unaffected parents. Phenotypic and genetic analyses were carried out to describe this condition and its molecular etiology. Genealogical, clinical and histological examinations confirmed the diagnosis of recessive JEB, even if affected calves showed milder symptoms than those of another form of JEB, previously reported in the same breed, and due to a homozygous deletion of ITGB4. Homozygosity mapping followed by analysis of the whole genome sequences of 2 cases and 5031 control individuals enabled us to prioritize a splice donor site of ITGA6 (c.2160+1G>T; Chr2 g.24112740C>A) as the most compelling candidate variant. This substitution showed a perfect genotype-phenotype correlation in the two affected pedigrees and was found to segregate only in Charolais, and at a very low frequency (f=1.6*10-4) after genotyping 186,154 animals from 15 breeds. Finally, RT-PCR analyses revealed increased retention of ITGA6 introns 14 and 15 in a heterozygous mutant cow as compared with a matched control. The mutant mRNA is predicted to cause a frameshift (ITGA6 p.I657Mfs1) affecting the assembly of the Integrin α6β4 dimer and its correct anchoring to the cell membrane. This dimer is a key component of the hemidesmosome anchoring complex, which ensures the attachment of basal epithelial cells to the basal membrane. In conclusion, we report a rare example of partial phenocopies observed in the same breed and due to mutations affecting two members of the same protein dimer, as well as the first evidence of an ITGA6 mutation causing JEB in livestock species.
Domains
Life Sciences [q-bio]Origin | Files produced by the author(s) |
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