Brain Advance Access published online on May 12, 2009
Brain, doi:10.1093/brain/awp073
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CYP7B1 mutations in pure and complex forms of hereditary spastic paraplegia type 5
1 INSERM, UMR_S975 (formerly U679), Paris, France 2 UPMC Univ Paris 06, UMR_S975, Centre de Recherche Institut du Cerveau et de la Moelle, CNRS 7225, Pitié-Salpêtrière Hospital, Paris, France 3 Laboratoire de Génétique Humaine, Université Victor Segalen Bordeaux 2, Bordeaux, France 4 Department of Genetics and Cytogenetics, AP-HP, Pitié-Salpêtrière Hospital, Paris, France 5 Service de Neurologie, Hôpital Universitaire Habib Bourguiba, Sfax, Tunisia 6 Friedrich-Schiller-Universitat of Jena, Germany 7 Medical Genetics Department, St George's, University of London, London, UK 8 Service de Neurologie, CHU de Rouen, Rouen, France 9 INSERM U546, Paris, France 10 British Hospital, Lisbon, Portugal 11 Service de Génétique Médicale, CHU Nantes, Nantes, France 12 Service d’Hépatologie, AP-HP, Hôpital Saint Antoine, Paris, France 13 Faculté de Médecine Pierre et Marie Curie, Paris, France and Service d’Anatomie Pathologique, Hôpital Saint-Antoine, AP-HP, Faculté de Médecine Pierre et Marie Curie, Paris, France 14 Genethon, Evry, France 15 Service commun de Spectrométrie de Masse, INSERM, UPMC, Paris, France 16 Institute of Human Genetics, Newcastle General Hospital, UK 17 Hosp. S. Sebastiao, Santa Maria da Feira, Portugal 18 Service de Neurologie et Pathologie du Mouvement, hôpital de la Timone, 13385 Marseille cedex 05, France
Correspondence to:
Dr Giovanni Stevanin, INSERM/UPMC UMR_S 975 (ex U679), CRicm, Bat. Pharmacie, Pitié-Salpêtrière Hospital, 47 Bd de l’Hôpital 75651 Paris Cedex 13, France. E-mail: giovanni.stevanin{at}upmc.fr
Thirty-four different loci for hereditary spastic paraplegias have been mapped, and 16 responsible genes have been identified. Autosomal recessive forms of spastic paraplegias usually have clinically complex phenotypes but the SPG5, SPG24 and SPG28 loci are considered to be associated with ‘pure’ forms of the disease. Very recently, five mutations in the CYP7B1 gene, encoding a cytochrome P450 oxysterol 7-
hydroxylase and expressed in brain and liver, have been found in SPG5 families. We analysed the coding region and exon–intron boundaries of the CYP7B1 gene by direct sequencing in a series of 82 unrelated autosomal recessive hereditary spastic paraplegia index patients, manifesting either a pure (n = 52) or a complex form (n = 30) of the disease, and in 90 unrelated index patients with sporadic pure hereditary spastic paraplegia. We identified eight, including six novel, mutations in CYP7B1 segregating in nine families. Three of these mutations were nonsense (p.R63X, p.R112X, p.Y275X) and five were missense mutations (p.T297A, p.R417H, p.R417C, p.F470I, p.R486C), the last four clustering in exon 6 at the C-terminal end of the protein. Residue R417 appeared as a mutational hot-spot. The mean age at onset in 16 patients was 16.4 ± 12.1 years (range 4–47 years). After a mean disease duration of 28.3 ± 13.4 years (10–58), spasticity and functional handicap were moderate to severe in all cases. Interestingly, hereditary spastic paraplegia was pure in seven SPG5 families but complex in two. In addition, white matter hyperintensities were observed on brain magnetic resonance imaging in three patients issued from two of the seven pure families. Lastly, the index case of one family had a chronic autoimmune hepatitis while his eldest brother died from cirrhosis and liver failure. Whether this association is fortuitous remains unsolved, however. The frequency of CYP7B1 mutations were 7.3% (n = 6/82) in our series of autosomal recessive hereditary spastic paraplegia families and 3.3% (n = 3/90) in our series of sporadic pure spastic paraplegia. The recent identification of CYP7B1 as the gene responsible for SPG5 highlights a novel molecular mechanism involved in hereditary spastic paraplegia determinism.
Key Words: CYP7B1; SPG5; hereditary spastic paraplegia; autosomal recessive spastic paraplegia; cholesterol metabolism
Abbreviations:
AR-HSP, autosomal recessive hereditary spastic paraplegias; CTX, cerebrotendinous xanthomatosis; CYP7B1, cytochrome P450 7-hydroxylase B1; DHEA, dehydroepiandrosterone; ENMG, electromyography; ESE, exonic splicing enhancers; HSP, hereditary spastic paraplegias; MRI, magnetic resonance imaging; PNP, peripheral neuropathy; SPG, spastic paraplegia gene; WMH, white matter hyperintensities
Received October 15, 2008. Revised February 10, 2009. Accepted February 19, 2009.
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