SHH and holoprosencephaly: It has also been suggested that PTCH1 (functioning in cilia) might inhibit SMO enzymatically in an ultrasensitive regime to remove cholesterol from the extracellular cysteine-rich domain of SMO to deactivate SMO, such that PTCH1 mutants with holoprosencephaly might show a reduced affinity for the SHH ligand, an increased catalytic activity or an increased affinity for SMO [66].