PITX1-Associated Congenital Lower Limb Malformations

Abstract

Abstract PITX1 belongs to the paired-like homeodomain transcription factor family that contains three genes that have all been linked to human disease. Because of its preferential lower limb expression, PITX1 missense mutations and deletions result in a spectrum of human lower limb malformations, including isolated clubfoot, preaxial polydactyly, mirror image polydactyly, and tibial hemimelia. Asymmetric involvement with the right lower limb being more affected is common in malformations involving PITX1alterations, likely due to partial compensation by the asymmetrically expressed PITX2 gene. Interestingly, misexpression of PITX1 in the upper limb causes homeotic arm-to-leg transformations associated with Liebenberg syndrome. Similar lower limb malformations, including isolated clubfoot, may also result from abnormal expression of the T-box transcription factor gene, TBX4, that is a known transcriptional target of PITX1. Emerging evidence also points to a role for PITX1 as a tumor suppressor in cancer.