Heart- and neural crest derivatives-expressed protein 2 is a protein that in humans is encoded by the HAND2 gene. Function The protein encoded by this gene belongs to the basic helix-loop-helix family of transcription factors. This gene product is one of two closely related family members, the HAND proteins Hand1 and Hand2, which are asymmetrically expressed in the developing ventricular chambers and play an essential role in cardiac morphogenesis. Working in a complementary fashion, they function in the formation of the right ventricle and aortic arch arteries, implicating them as mediators of congenital heart disease. In addition, this transcription factor plays an important role in limb and branchial arch development. In one study, it was found that a missense mutation of the Hand2 protein in patients with the congenital heart disease (CHD) Tetralogy of Fallot experienced significantly decreased Hand2 interactions with other key developmental genes such as GATA4 and NKX2.5. Hand2 mutations have the potential to be genes for the future study of right ventricle stenosis and its pathogenesis. In avian species, Hand2 has been shown to be expressed in developing gut tissue and is believed to contribute to the formation of enteric neurons. Hand2 also plays a critical role in the establishment of a proper implantation environment for pregnancy in mice. The induction of Hand2 by progesterone-dependent mechanisms in uterine stromal tissue suppresses fibroblast growth factors (FGFs) that would otherwise stimulate estrogen producing pathways and impair embryo implantation. Hand2 plays a role in lower jaw formation and tongue morphogenesis in mice by suppressing the homeobox genes Dlx5 and Dlx6. Interactions HAND2 has been shown to interact with GATA4, NKX2.5, PPP2R5D, PHOX2A., TWIST1, and TWIST2. Clinical significance Hand2 interactions with TWIST1 and TWIST2 genes are critical for proper limb development. Recent literature shows over dosage of Hand2 can result in many defects in the limbs, face, heart, and lower lumbar vertebrae. In this instance, trisomy of the hand2 gene can directly cause human congenital heart disease. Hand2 gene hypermethylation and epigenetic silencing has also been implicated to increase the development of endometrial cancer. Mounting evidence showing its methylation increased chances of premalignant endometrial lesions. Hand2, in addition to its other functions in the developing heart and limbs, has been found to be an important transcription factor seen in the endometrial stroma. In fact, in mice with the Hand2 gene knocked out, they developed premalignant lesions as they grew older, further