We performed association and haplotype analysis for the MHC region to identify risk haplotypes using AA patients and controls. Next, we sequenced the risk and control haplotypes to identify AA-susceptibility variants. Then, we engineered mice carrying the human risk allele using allele-specific genome editing with the CRISPR/Cas9 system to reproduce AA phenotype. Among the large number of variants there was only one nonsynonymous variant identical in the AA risk haplotype. The variant is located in the coiled-coil alpha-helical rod protein 1 (CCHCR1) gene. Next, mice were generated with the risk allele concordant with the variant of CCHCR1 in humans, then we established mouse strains with risk alleles (AA mice). Half of AA mice displayed patched hair loss until 10 months after birth, thus successfully phenocopying the hair loss phenotype.

MHC risk haplotype sequencing and allele-specific genome editing by CRISPR/Cas9 system reveal cchcr1 as susceptibility gene for alopecia areata.