SHH and holoprosencephaly: Related to this Pineda-Alvarez et al. [34] and Ribeiro et al. [35] reported missense mutations of GAS1 in holoprosencephaly (HPE) patients.In particular Thr200Arg mutation in the second domain of GAS1 Pineda-Alvarez et al. [34] was observed to result in almost complete loss of binding affinity for SHH, hence this domain could also be important for binding to SHH.