Zone of Polarizing Activity Regulatory Sequence Mutations/Duplications with Preaxial Polydactyly and Longitudinal Preaxial Ray Deficiency in the Phenotype: A Review of Human Cases, Animal Models, and Insights Regarding the Pathogenesis

Figure 3

The interactions between the LPAD and PPD loops may explain the PPD-LPAD association related to ZRS mutations/duplications (see text for details). Note that both loops share SALL1 and GLI3. Deficiency of SALL1 (within the LPAD loop) will affect both the expression of SHH and the HOX system as described by Kawakami et al. [11]. Hence, the Townes-Brocks phenotype may present as LPAD only, PPD only, or PPD-LPAD association. GLI3 deficiency will result in anterior ectopic expression of SHH and PPD, since GLI3 is a negative regulator of SHH. Simultaneously, GLI3 deficiency may result in SALL4 deficiency as described by Akiyama et al. [12]. Hence, GLI3 is another important link between the two loops.