Structure of the human Lanosterol Synthase gene and its analysis as a candidate for holoprosencephaly (HPE1)

Holoprosencephaly (HPE) is the most common birth defect of the brain in hum ans. It involves various degrees of incomplete separation of the cerebrum i nto distinct left and right halves, and it is frequently accompanied by cra niofacial anomalies. The HPE1 locus in human chromosome 21q22.3 is one of a dozen putative genetic loci implicated in causing HPE. Here, we report the complete gene structure of the human lanosterol synthase (LS) gene, which is located in this interval, and present its mutational analysis in HPE pat ients. We considered LS an excellent candidate HPE gene because of the requ irement for cholesterol modification of the Sonic Hedgehog protein for the correct patterning activity of this HPE-associated protein. Despite extensi ve pedigree analysis of numerous polymorphisms, as well as complementation studies in yeast on one of the missense mutations, we find no evidence that the LS gene is in fact HPE1, implicating another gene located in this chro mosomal region in HPE pathogenesis.