Limb, genital, CNS, and facial malformations result from gene/environment-induced cholesterol deficiency: Further evidence for a link to sonic hedgehog

Abstract

Low cholesterol levels produced by treating cholesterol deficient mutant mice with a cholesterol synthesis inhibitor (BM 15.766) between days 4 to 7 of pregnancy resulted in malformations consistent with those in the Smith-Lemli-Opitz syndrome (SLOS). Facial anomalies in mildly affected gestational day 12 mouse embryos included a small nose and long upper lip; in more severely affected embryos, the facial and forebrain anomalies are representative of holoprosencephaly. Additionally, abnormalities of the mid- and hind-brain were observed and included stenosis of the cerebral aqueduct at the level of the isthmus and apparent absence of the organ progenitor for the cerebellar vermis. Although not 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 cholesterol in early embryonic development, provide additional support for the hypothesis that this role may involve the function of specific gene products, such as sonic hedgehog (shh) signaling protein, and provide a description of the pathogenesis of some of the characteristic malformations in SLOS.

Malformation syndromes caused by disorders of cholesterol synthesis

“…Pharmacological inhibitors of DHCR7 that have been used to model SLOS include YM9429 ( 110,111 ), BM15.766 (112)(113)(114)(115), and AY9944 (116)(117)(118)(119). All three of these compounds appear to be noncompetitive inhibitors of DHCR7 ( 110,120 ).…”

Cholesterol Biosynthesis from Lanosterol

“…This connection between cholesterol and the developmental program in mammals was established based on the critical role of cholesterol in autoprocessing of sonic hedgehog (shh) protein (5,6,19), a morphogen, which binds to, patched protein in developing the central nervous system and limbs. For example, the mouse mutated in shh showed SLOS-like phenotype (20,21).…”

An MCA/MR syndrome with hypocholesterolemia due to familial hypobetalipoproteinemia: Report of a second patient with Nguyen syndrome

“…In mice, apo B deficiency phenotype appeared to involve the hindbrain, which is similar to that of vitamin E deficiency [Homanics et al, 1995]. Apo B mutant mice treated with a cholesterol synthesis inhibitor between day 4 and 7 of pregnancy demonstrated malformations consistent with those in SLOS, including facial and forebrain anomalies [Lanoue et al, 1997]. Cholesterol deficiency due to ADHBL itself is not sufficient to develop an SLOS-like phenotype in mice.…”