Exome sequencing identifies a TCF4 mutation in a Chinese pedigree with symmetrical acral keratoderma

Background Symmetrical acral keratoderma (SAK) is a rare skin disorder and its pathogenesis and inheritability are unknown. Objectives To investigate the inheritance and pathogenesis of SAK. Methods Four SAK cases occurred in a four-generation Chinese family. Exome sequencing identified SNPs with potential SAK-related mutations, and a potentially responsible gene transcription factor 4 (TCF4) was identified. TCF4 was then sequenced in all 11 family members, and pedigree analysis was performed. Histopathology and immunohistochemistry evaluated TCF4 expression in skin lesions. The gene mutation was investigated in human keratinocytes for keratin-related protein expression. Results A novel heterozygous missense mutation, c.85C>A (p.Pro29Thr) was found in TCF4. The mutation showed autosomal dominant inheritance and perfectly cosegregated with the SAK phenotype in all family members. In skin lesions, TCF4 was present in the cytoplasm and membranes of the basal layer, the stratum spinosum and the stratum granulosum of the epidermis. The mutant TCF4 induced overexpression of differentiation markers including KRT1, KRT14, loricrin and involucrin. Conclusions A SAK-related gene mutation in TCF4 may function through transcriptional regulation of keratin.