Mutations in the C-terminal domain of Sonic Hedgehog cause holoprosencephaly

Holoprosencephaly (HPE) is the most common brain anomaly in humans,involving abnormal formation and septation of the developing centralnervous system. Among the heterogeneous causes of HPE, mutations in theSonic Hedgehog (SHH) gene have been shown to result in an autosomaldominant form of the disorder. Here we describe a total of five differentmutations in the processing domain encoded by exon 3 of SHH in familial andsporadic HPE. This is the first instance in humans where SHH mutations inthe domain responsible for autocatalytic cleavage and cholesterolmodification of the N-terminal signaling domain of the protein have beenobserved.