LIMB, GENITAL, CNS, AND FACIAL MALFORMATIONS RESULT FROM GENE ENVIRONMENT-INDUCED CHOLESTEROL DEFICIENCY - FURTHER EVIDENCE FOR A LINK TO SONIC HEDGEHOG/

Low cholesterol levels produced by treating cholesterol deficient muta nt mice with a cholesterol synthesis inhibitor (BM 15.766) between day s 4 to 7 of pregnancy resulted in malformations consistent with those in the Smith-Lemli-Opitz syndrome (SLOS). Facial anomalies in mildly a ffected gestational day 12 mouse embryos included a small nose and lon g upper lip; in more severely affected embryos, the facial and forebra in anomalies are representative of holoprosencephaly. Additionally, ab normalities of the mid-and hind-brain were observed and included steno sis of the cerebral aqueduct at the level of the isthmus and apparent absence of the organ progenitor for the cerebellar vermis. Although no t previously directly linked to cholesterol deficiency in experimental animals, limb and external genital defects were a notable outcome in this multifactorially-based cholesterol deficiency model. The results of this study provide new evidence supporting an important role for ch olesterol in early embryonic development, provide additional support f or the hypothesis that this role may involve the function of specific gene products, such as sonic hedgehog (shh) signaling protein, and pro vide a description of the pathogenesis of some of the characteristic m alformations in SLOS. (C) 1997 Wiley-Liss, Inc.