Sequence Alterations within CYP7B1 Implicate Defective Cholesterol Homeostasis in Motor-Neuron Degeneration
Maria Tsaousidou,Karim Ouahchi,Thomas T. Warner,Yi Yang,Michael A. Simpson,Nigel G. Laing,Philip A. Wilkinson,Ricardo E. Madrid,Heema Patel,Fayçal Hentati,Michael A. Patton,Afif Hentati,Philippa J. Lamont,Teepu Siddique,Andrew H. Crosby +14 more
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TL;DR: 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 pure form of HSP.
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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.
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Citations
Hereditary spastic paraplegia: clinical features and pathogenetic mechanisms
TL;DR: The clinical and diagnostic features of the various forms of HSP are described and the genes that have been identified and the emerging pathogenic mechanisms are discussed.
565
Human cytochromes P450 in health and disease
TL;DR: There are 18 mammalian cytochrome P450 (CYP) families, which encode 57 genes in the human genome, but the CYP2, CYP3 and CYP4 families contain far more genes than the other 15 families; these three families are also the ones that are dramatically larger in rodent genomes.
489
Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms.
TL;DR: Hereditary spastic paraplegia is a syndrome designation describing inherited disorders in which lower extremity weakness and spasticity are the predominant symptoms and emerging concepts of this large group of clinically similar disorders are highlighted.
Hereditary spastic paraplegia: Clinical-genetic characteristics and evolving molecular mechanisms
Temistocle Lo Giudice,Federica Lombardi,Filippo M. Santorelli,Toshitaka Kawarai,Antonio Orlacchio +4 more
TL;DR: Interactome networks have been postulated by bioinformatics and biological analyses of spastic paraplegia genes, which would contribute to the development of new therapeutic approaches.
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Hereditary spastic paraplegias: membrane traffic and the motor pathway
TL;DR: Hereditary spastic paraplegias are a group of genetic disorders that lead to a length-dependent, distal axonopathy of fibres of the corticospinal tract, causing lower limb spasticity and weakness.
References
Human cholesterol 7α-hydroxylase (CYP7A1) deficiency has a hypercholesterolemic phenotype
Clive R. Pullinger,Celeste Eng,Gerald Salen,Sarah Shefer,Ashok K. Batta,Sandra K. Erickson,Andrea Verhagen,Christopher R. Rivera,Sean J. Mulvihill,Mary J. Malloy,John P. Kane +10 more
TL;DR: A new metabolic disorder presenting with hyperlipidemia caused by a homozygous deletion mutation in CYP7A1 is reported, which leads to a frameshift that results in loss of the active site and enzyme function.
Mutations in the bile acid biosynthetic enzyme sterol 27-hydroxylase underlie cerebrotendinous xanthomatosis.
TL;DR: The identification of different point mutations in the gene (CYP27) encoding sterol 27-hydroxylase, a key enzyme in the bile acid biosynthesis pathway, underscores the essential role played by sterols in the central nervous system and suggests that mutations in other sterol metabolizing enzymes may contribute to diseases with neurological manifestations.
501
Identification of a new inborn error in bile acid synthesis: mutation of the oxysterol 7alpha-hydroxylase gene causes severe neonatal liver disease.
Kenneth D.R. Setchell,Margrit Schwarz,Nancy C. O'Connell,Erik G. Lund,Daphne L. Davis,Richard Lathe,Henry R. Thompson,R. Weslie Tyson,Ronald J. Sokol,David W. Russell +9 more
TL;DR: The findings indicate the quantitative importance of the acidic pathway in early life in humans and define a further inborn error in bile acid synthesis as a metabolic cause of severe cholestatic liver disease.
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