Sonic hedgehog signal peptide mutation in a patient with holoprosencephaly

We investigated the molecular basis of holoprosencephaly in a sporadic pati ent and identified a novel missense mutation in the signal sequence of the sonic hedgehog (Shh) gene. Magnetic resonance imaging of the head showed a lobar type of holoprosencephaly and partial agenesis of the anterior corpus callosum. He was treated for craniosynostosis at 7 months of age. hll thre e exons of the Shh gene mere amplified by polymerase chain reaction from ge nomic DNA of the patient and controls. Sequencing analysis of the polymeras e chain reaction fragments, screened by single-strand conformation polymorp hism analysis, revealed a heterozygous mutation of a T-to-C substitution at nucleotide position 50. This mutation predicted an amino acid replacement of leucine to proline at codon 17 located in the signal peptide of SHH prot ein. It probably disturbs the translocation of the protein into the endopla smic reticulum and may lead to holoprosencephaly because of haploinsufficie ncy of Shh.