HOLOPROSENCEPHALY IN RSH SMITH-LEMLI-OPITZ-SYNDROME - DOES ABNORMAL CHOLESTEROL-METABOLISM AFFECT THE FUNCTION OF SONIC-HEDGEHOG/

The RSH/Smith-Lemli-Opitz syndrome (RSH/SLOS) is an autosomal recessiv e malformation syndrome associated with increased levels of 7-dehydroc holesterol (7-DHC) and a defect of cholesterol biosynthesis at the lev el of 3beta-hydroxy-steroid-triangle(7)-reductase (7-DHC reductase). B ecause rats exposed to inhibitors of 7-DHC reductase during developmen t have a high frequency of holoprosencephaly (HPE) [Roux et al., 1979] , we have undertaken a search for biochemical evidence of RSH/SLOS and other possible defects of sterol metabolism among patients with vario us forms of HPE. We describe 4 patients, one with semilobar HPE and th ree others with less complete forms of the HPE sequence, in whom we ha ve made a biochemical diagnosis of RSH/SLOS. The clinical and biochemi cal spectrum of these and other patients with RSH/SLOS suggests a role of abnormal sterol metabolism in the pathogenesis of their malformati ons. The association of HPE and RSH/SLOS is discussed in light of the recent discoveries that mutations in the embryonic patterning gene, So nic Hedgehog (SHH), can cause HPE in humans and that the sonic hedgeho g protein product undergoes autoproteolysis to form a cholesterol-modi fied active product. These clinical, biochemical, and molecular studie s suggest that HPE and other malformations in SLOS may be caused by in complete or abnormal modification of the sonic hedgehog protein and, p ossibly, other patterning proteins of the hedgehog class, a hypothesis testable in somatic cell systems.