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First published online April 24, 2006
doi: 10.1242/10.1242/jcs.02906

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Abnormal sterols in cholesterol-deficiency diseases cause secretory granule malformation and decreased membrane curvature

Marjorie C. Gondré-Lewis^1,*, Horia I. Petrache², Christopher A. Wassif³, Daniel Harries², Adrian Parsegian², Forbes D. Porter³ and Y. Peng Loh^1,

¹ Section on Cellular Neurobiology, National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA
² Laboratory of Physical and Structural Biology, National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA
³ Heritable Disorders Branch, National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA

Author for correspondence (e-mail: lohp{at}mail.nih.gov)

Accepted 27 January 2006

Cholesterol is an abundant lipid in eukaryotic membranes, implicated in numerous structural and functional capacities. Here, we have investigated the mechanism by which cholesterol affects secretory granule biogenesis in vivo using Dhcr7^-/- and Sc5d^-/- mouse models of the human diseases, Smith-Lemli-Opitz syndrome (SLOS) and lathosterolosis. These homozygous-recessive multiple-malformation disorders are characterized by the functional absence of one of the last two enzymes in the cholesterol biosynthetic pathway, resulting in the accumulation of precursors. Cholesterol-deficient mice exhibit a significant decrease in the numbers of secretory granules in the pancreas, pituitary and adrenal glands. Moreover, there was an increase in morphologically aberrant granules in the exocrine pancreas of Dhcr7^-/- acinar cells. Regulated secretory pathway function was also severely diminished in these cells, but could be restored with exogenous cholesterol. Sterol precursors incorporated in artificial membranes resulted in decreased bending rigidity and intrinsic curvature compared with cholesterol, thus providing a cholesterol-mediated mechanism for normal granule budding, and an explanation for granule malformation in SLOS and lathosterolosis.

Key words: Cholesterol, Granule biogenesis, Membrane curvature, Regulated secretory pathway, Smith-Lemli-Opitz syndrome (SLOS), Lathosterolosis

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