Cholesterol precursors and facial clefting

Abstract

Inborn errors of cholesterol synthesis cause human malformation syndromes, including Smith-Lemli-Opitz syndrome, lathosterolosis, desmosterolosis, X-linked dominant chondrodysplasia punctata type 2, and congenital hemidysplasia with ichthyosiform erythroderma and limb defects. Because adequate cholesterol is not transported across the placenta, low cholesterol and elevated sterol precursor levels are present during embryogenesis. It has been debated whether the malformations result from low cholesterol or the buildup of sterol precursors. In this issue of the JCI, Engelking et al. provide evidence that sterol precursor accumulation plays a pivotal role in the genesis of facial malformations (see the related article beginning on page 2356).

Figure 1. SLOS phenotype.

Typical facial features of a SLOS patient as an infant (A) and young child (B). Cutaneous syndactyly of the second and third toes (C) is the most frequently reported finding in SLOS. Hand anomalies (D and E) may include single palmar creases, short thumbs, and postaxial polydactyly. Some degree of cleft palate (F) is observed in approximately half of the patients.

Figure 2. Insig regulation of cholesterol synthesis and Shh signaling.

When cholesterol levels are sufficient, Insig proteins regulate cholesterol synthesis by preventing the activation of SREBPs and promoting the degradation of HMG-CoA reductase (left). Cholesterol synthesis becomes dysregulated in Insig-DKO embryos (right). Even when cholesterol levels are elevated, activated SREBPs continue to promote the transcription of cholesterol synthetic genes, and HMG-CoA reductase activity remains high. This results in an accumulation of sterol precursors. The Shh signaling pathway is sensitive to perturbation of cholesterol homeostasis. In the signaling cell (left), Shh protein is modified by the addition of cholesterol. In the responding cell (right), Ptch maintains Smo in an inactive state (Smo_I), perhaps by preventing sterol binding. Shh binding to Ptch relieves this inhibition. Activation of Smo (Smo_A) promotes transcription of Shh-responsive genes through the Gli family of transcription factors. Adequate cholesterol or oxysterol levels appear to be necessary for Smo activation. Accumulating sterol precursors in the Insig-DKO embryos could, perhaps via a direct interaction with Smo, alter Shh signaling and underlie the genesis of facial clefting reported by Engelking et al. in Insig-DKO mice (6). Gli_I, inactive Gli; Gli_A, activated Gli.