However, Six homeobox 3 (SIX3) is known to bind to SBE2, and mutation of its binding site, or of SIX3 itself, affects Shh expression in the developing brain, leading to holoprosencephaly (HPE) (Geng et al., 2008, Jeong et al., 2008). Here, SHH is linked to holoprosencephaly.