The Hand2 gene dosage effect in developmental defects and human congenital disorders

Heart- and neural crest derivatives-expressed (Hand) proteins belong to the Twist family of the basic helix-loop-helix (bHLH) transcription factors, and play crucial roles in the development of several organs. They form heterodimers with Twist1 via their HLH domain. Disruption of the expression balance between Hand2 and Twist1 causes limb malformation, indicating that the expression level of Hand2 relative to Twist1 is essential for limb development. Mutations of the TWIST1 and TWIST2 genes are involved in human diseases. Although, the functions of the Hand proteins are indispensable for limb, heart, and craniofacial development, mutations of the Hand genes that are causative of human diseases remain elusive. Recently, comparative analyses of a human chromosomal disorder, partial trisomy distal 4q, and its mouse model, which is a spontaneously occurring mutant, clearly demonstrated that over dosage of Hand2 results in developmental defects of limbs, craniofacial, and lumbar vertebrae, and that trisomy of the Hand2 gene directly causes a human congenital disorder. In this review, we focus on gene dosage effect of Hand2 in limb, heart, and craniofacial development, and discuss its implication in human diseases.