Diverse dystonin gene mutations cause distinct patterns of isoform deficiency and phenotypic heterogeneity in mice.

Loss-of-function mutations in dystonin () can cause hereditary sensory and autonomic neuropathy type 6 (HSAN-VI) or epidermolysis bullosa simplex (EBS). Recently, -related diseases were recognized to be more complex than previously thought because a patient exhibited both neurological and skin manifestations, whereas others display only one or the other. A single locus produces at least three major isoforms: (neuronal isoform), (muscular isoform) and (epithelial isoform). () mice, which have mutations in , were originally identified as spontaneous mutants displaying neurological phenotypes. To reveal the mechanisms underlying the phenotypic heterogeneity of -related diseases, we investigated two mutant strains with different mutations: a spontaneous mutant ( mice) and a gene-trap mutant ( mice). The allele possesses a nonsense mutation in an exon shared by all isoforms. The allele is predicted to inactivate and isoforms but not There was a decrease in the levels of mRNA in the neural tissue of both and homozygotes. Loss of sensory and autonomic nerve ends in the skin was observed in both and mice at postnatal stages. In contrast, mRNA expression was reduced in the skin of mice but not in mice. Expression levels of Dst proteins in neural and cutaneous tissues correlated with mRNAs. Because encodes a structural protein in hemidesmosomes (HDs), we performed transmission electron microscopy. Lack of inner plaques and loss of keratin filament invasions underneath the HDs were observed in the basal keratinocytes of mice but not in those of mice; thus, the distinct phenotype of the skin of mice could be because of failure of Dst-e expression. These results indicate that distinct mutations within the locus can cause different loss-of-function patterns among isoforms, which accounts for the heterogeneous neural and skin phenotypes in mice and -related diseases.