Unveiling a New Link: Cholesterol Deficiency in Smith-Lemli-Opitz and Niemann-Pick C as a Driver of Ciliopathies

: The ciliopathies are a group of genetic disorders caused by defective function of either the primary cilia (a large number) or the motile cilia (a much smaller number). These have been defined as diseases with mutations in genes encoding individual ciliary or cilia-associated proteins. Recently, it has become apparent that the composition of the ciliary membrane influences its function. For instance, the ciliary membrane contains more cholesterol than other regions of the cell membrane and a variety of unique receptors and ion channels. Additionally, it appears that primary cilia have evolved to lower the threshold for activating signal transduction by establishing the environment essential for signaling pathways on a limited portion of the cell surface. By positioning receptors and downstream signaling components in this thin protrusion at a precise time and location within the plasma membrane, the cell can better orient its physiological response to external stimuli. Cholesterol deficiency can alter cilia formation and function with effects on Sonic hedgehog signaling. In this review, we discuss these new concepts and apply them to the developmental disorder Smith-Lemli-Opitz syndrome and the developmental and neurodegenerative disorder Niemann-Pick C disease, demonstrating that they are also ciliopathies.