Practice question

Clubfoot talipes equinovarus involves abnormal hindlimb tendon, muscle and skeletal patterning linked to reduced Pitx1 pathway dosage. Human genome-wide association and mouse models show Pitx1 haploinsufficiency or cis-regulatory enhancer mutations produce shortened hindlimbs, abnormal calf muscle morphology, altered Achilles tendon insertion and foot malrotation resembling clubfoot deformity with dorsal flexion. TBX5 causes Holt-Oram forelimb defects, SHH affects anterior-posterior digit number, PAX6 governs eye development. PITX1 regulation of Tbx4 and hindlimb-specific effectors including Tbx2 makes it key gene associated with clubfoot and hindlimb malformations across species.