Analysis of Smoothened as a candidate gene for human holoprosencephaly

Holoprosencephaly (HPE) is the most common structural congenital forebrain malformation in humans and is associated with mental retardation and craniofacial abnormalities. In HPE, the cerebral hemispheres fail to separate into distinct right and left halves. The condition is etiologically heterogeneous, as multiple genes and environmental factors are associated with the condition. Autosomal dominant HPE can be caused by mutations in Sonic Hedgehog (SHH). Smoothened (SMOH; human gene) encodes a transmembrane protein that acts in SHH signal transduction. Because of the critical role of SMOH in the SHH pathway, we performed mutation analysis of this gene in familial and sporadic cases of HPE. Although we identified a number of nucleotide changes in SMOH in affected patients, none of these changes is likely to be pathogenic. Thus, haploinsufficiency for SMOH is unlikely to be a significant cause of human HPE in live-born infants.