@article{80b7861b961747e1b039e1f88d6fb540,
title = "Sequence Alterations within CYP7B1 Implicate Defective Cholesterol Homeostasis in Motor-Neuron Degeneration",
abstract = "The hereditary spastic paraplegias (HSPs) are a genetically and clinically heterogeneous group of upper-motor-neuron degenerative diseases characterized by selective axonal loss in the corticospinal tracts and dorsal columns. Although numerous mechanisms involving defective subcellular transportation, mitochondrial malfunction, and increased oxidative stress have been proposed, the pathogenic basis underlying the neuronal loss is unknown. We have performed linkage analysis to refine the extent of the SPG5 disease locus and conducted sequence analysis of the genes located within this region. This identified sequence alterations in the cytochrome P450-7B1 (CYP7B1) associated with this pure form of HSP. In the liver, CYP7B1 offers an alternative pathway for cholesterol degradation and also provides the primary metabolic route for the modification of dehydroepiandrosterone neurosteroids in the brain. These findings provide the first direct evidence of a pivotal role of altered cholesterol metabolism in the pathogenesis of motor-neuron degenerative disease and identify a potential for therapeutic intervention in this form of HSP.",
author = "Tsaousidou, {Maria K.} and Karim Ouahchi and Warner, {Tom T.} and Yi Yang and Simpson, {Michael A.} and Laing, {Nigel G G.} and Wilkinson, {Philip A.} and Madrid, {Ricardo E.} and Heema Patel and Faycal Hentati and Patton, {Michael A A.} and Afif Hentati and Lamont, {Philippa J.} and Teepu Siddique and Crosby, {Andrew H.}",
note = "Funding Information: The authors are grateful to the family members of the English, American, Australian, and Tunisian kindreds for participation in this research project and Dr. Phillipa J. Lamont of the Royal Perth Hospital of Australia. This work was supported at St George's in London by the Birth Defects Newlife Foundation (UK) and Action Research, and at Northwestern University Feinberg School of Medicine (in part) by The National Institutes of Health (NS046535, NS050641, and ES014469), The Les Turner ALS Foundation, Vena E. Schaff ALS Research Fund, Harold Post Research Professorship Fund, Herbert and Florence C. Wenske Foundation, Ralph and Marian Falk Medical Research Trust, The David C. Asselin MD Memorial Fund, and the Les Turner ALS Foundation/Herbert C. Wenske Foundation Professor . N.G.L. was supported by Australian National Health and Medical Research Council Fellowship 403904. ",
year = "2008",
month = feb,
day = "8",
doi = "10.1016/j.ajhg.2007.10.001",
language = "English (US)",
volume = "82",
pages = "510--515",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "2",
}