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Analysis of CYP7B1 in non-consanguineous cases of hereditary spastic paraplegia

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Abstract

Hereditary spastic paraplegia (HSP) is a neurodegenerative condition defined clinically by lower limb spasticity and weakness. Homozygous mutations in CYP7B1 have been identified in several consanguineous families that represented HSP type 5 (SPG5), one of the many genetic forms of the disease. We used direct sequencing and multiplex ligation-dependent probe amplification to screen for CYP7B1 alterations in apparently sporadic HSP patients (n = 12) as well as index patients from non-consanguineous families with recessive (n = 8) and dominant (n = 8) transmission of HSP. One sporadic patient showing HSP as well as optic atrophy carried a homozygous nonsense mutation. Compound heterozygosity was observed in a recessive family with a clinically pure phenotype. A heterozygous missense change segregated in a small dominant family. We also found a significant association of a known coding polymorphism with cerebellar signs complicating a primary HSP phenotype. Our findings suggest CYP7B1 alterations to represent a rather frequent cause of HSP that should be considered in patients with various clinical presentations.

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References

  1. Fink JK (2006) Hereditary spastic paraplegia. Curr Neurol Neurosci Rep 6:65–76, doi:10.1007/s11910-996-0011-1

    Article  CAS  PubMed  Google Scholar 

  2. Depienne C, Stevanin G, Brice A, Durr A (2007) Hereditary spastic paraplegias: an update. Curr Opin Neurol 20:674–680

    Article  CAS  PubMed  Google Scholar 

  3. Tsaousidou MK, Ouahchi K, Warner TT, Yang Y, Simpson MA, Laing NG, Wilkinson PA, Madrid RE, Patel H, Hentati F, Patton MA, Hentati A, Lamont PJ, Siddique T, Crosby AH (2008) Sequence alterations within CYP7B1 implicate defective cholesterol homeostasis in motor-neuron degeneration. Am J Hum Genet 82:510–515, doi:10.1016/j.ajhg.2007.10.001

    Article  CAS  PubMed  Google Scholar 

  4. Hanein S, Martin E, Boukhris A, Byrne P, Goizet C, Hamri A, Benomar A, Lossos A, Denora P, Fernandez J, Elleuch N, Forlani S, Durr A, Feki I, Hutchinson M, Santorelli FM, Mhiri C, Brice A, Stevanin G (2008) Identification of the SPG15 gene, encoding spastizin, as a frequent cause of complicated autosomal-recessive spastic paraplegia, including Kjellin syndrome. Am J Hum Genet 82:992–1002, doi:10.1016/j.ajhg.2008.03.004

    Article  CAS  PubMed  Google Scholar 

  5. Casari G, De Fusco M, Ciarmatori S, Zeviani M, Mora M, Fernandez P, De Michele G, Filla A, Cocozza S, Marconi R, Durr A, Fontaine B, Ballabio A (1998) Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease. Cell 93:973–983, doi:10.1016/S0092-8674(00)81203-9

    Article  CAS  PubMed  Google Scholar 

  6. Fonknechten N, Mavel D, Byrne P, Davoine CS, Cruaud C, Bonsch D, Samson D, Coutinho P, Hutchinson M, McMonagle P, Burgunder JM, Tartaglione A, Heinzlef O, Feki I, Deufel T, Parfrey N, Brice A, Fontaine B, Prud'homme JF, Weissenbach J, Durr A, Hazan J (2000) Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia. Hum Mol Genet 9:637–644, doi:10.1093/hmg/9.4.637

    Article  CAS  PubMed  Google Scholar 

  7. Sauter SM, Engel W, Neumann LM, Kunze J, Neesen J (2004) Novel mutations in the Atlastin gene (SPG3A) in families with autosomal dominant hereditary spastic paraplegia and evidence for late onset forms of HSP linked to the SPG3A locus. Hum Mutat 23:98, doi:10.1002/humu.9205

    Article  CAS  PubMed  Google Scholar 

  8. Beetz C, Schule R, Deconinck T, Tran-Viet KN, Zhu H, Kremer BP, Frints SG, van Zelst-Stams WA, Byrne P, Otto S, Nygren AO, Baets J, Smets K, Ceulemans B, Dan B, Nagan N, Kassubek J, Klimpe S, Klopstock T, Stolze H, Smeets HJ, Schrander-Stumpel CT, Hutchinson M, van de Warrenburg BP, Braastad C, Deufel T, Pericak-Vance M, Schols L, de Jonghe P, Zuchner S (2008) REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31. Brain 131:1078–1086, doi:10.1093/brain/awn026

    Article  PubMed  Google Scholar 

  9. Hentati A, Pericak-Vance MA, Hung WY, Belal S, Laing N, Boustany RM, Hentati F, Ben Hamida M, Siddique T (1994) Linkage of ‘pure’ autosomal recessive familial spastic paraplegia to chromosome 8 markers and evidence of genetic locus heterogeneity. Hum Mol Genet 3:1263–1267, doi:10.1093/hmg/3.8.1263

    Article  CAS  PubMed  Google Scholar 

  10. Klebe S, Durr A, Bouslam N, Grid D, Paternotte C, Depienne C, Hanein S, Bouhouche A, Elleuch N, Azzedine H, Poea-Guyon S, Forlani S, Denis E, Charon C, Hazan J, Brice A, Stevanin G (2007) Spastic paraplegia 5: locus refinement, candidate gene analysis and clinical description. Am J Med Genet B Neuropsychiatr Genet 144B:854–861, doi:10.1002/ajmg.b.30518

    Article  PubMed  Google Scholar 

  11. Coutinho P, Barros J, Zemmouri R, Guimaraes J, Alves C, Chorao R, Lourenco E, Ribeiro P, Loureiro JL, Santos JV, Hamri A, Paternotte C, Hazan J, Silva MC, Prud'homme JF, Grid D (1999) Clinical heterogeneity of autosomal recessive spastic paraplegias: analysis of 106 patients in 46 families. Arch Neurol 56:943–949, doi:10.1001/archneur.56.8.943

    Article  CAS  PubMed  Google Scholar 

  12. Wilkinson PA, Crosby AH, Turner C, Patel H, Wood NW, Schapira AH, Warner TT (2003) A clinical and genetic study of SPG5A linked autosomal recessive hereditary spastic paraplegia. Neurology 61:235–238

    CAS  PubMed  Google Scholar 

  13. Muglia M, Criscuolo C, Magariello A, De Michele G, Scarano V, D'Adamo P, Ambrosio G, Gabriele AL, Patitucci A, Mazzei R, Conforti FL, Sprovieri T, Morgante L, Epifanio A, La Spina P, Valentino P, Gasparini P, Filla A, Quattrone A (2004) Narrowing of the critical region in autosomal recessive spastic paraplegia linked to the SPG5 locus. Neurogenetics 5:49–54, doi:10.1007/s10048-003-0167-7

    Article  CAS  PubMed  Google Scholar 

  14. Beetz C, Nygren AO, Schickel J, Auer-Grumbach M, Burk K, Heide G, Kassubek J, Klimpe S, Klopstock T, Kreuz F, Otto S, Schule R, Schols L, Sperfeld AD, Witte OW, Deufel T (2006) High frequency of partial SPAST deletions in autosomal dominant hereditary spastic paraplegia. Neurology 67:1926–1930, doi:10.1212/01.wnl.0000244413.49258.f5

    Article  CAS  PubMed  Google Scholar 

  15. Schule R, Holland-Letz T, Klimpe S, Kassubek J, Klopstock T, Mall V, Otto S, Winner B, Schols L (2006) The Spastic Paraplegia Rating Scale (SPRS): a reliable and valid measure of disease severity. Neurology 67:430–434, doi:10.1212/01.wnl.0000228242.53336.90

    Article  CAS  PubMed  Google Scholar 

  16. Beetz C, Schule R, Klebe S, Klimpe S, Klopstock T, Lacour A, Otto S, Sperfeld AD, van de Warrenburg B, Schols L, Deufel T (2008) Screening of hereditary spastic paraplegia patients for alterations at NIPA1 mutational hotspots. J Neurol Sci 268:131–135, doi:10.1016/j.jns.2007.11.015

    Article  CAS  PubMed  Google Scholar 

  17. Elleuch N, Depienne C, Benomar A, Hernandez AM, Ferrer X, Fontaine B, Grid D, Tallaksen CM, Zemmouri R, Stevanin G, Durr A, Brice A (2006) Mutation analysis of the paraplegin gene (SPG7) in patients with hereditary spastic paraplegia. Neurology 66:654–659, doi:10.1212/01.wnl.0000201185.91110.15

    Article  CAS  PubMed  Google Scholar 

  18. Arnoldi A, Tonelli A, Crippa F, Villani G, Pacelli C, Sironi M, Pozzoli U, D'Angelo MG, Meola G, Martinuzzi A, Crimella C, Redaelli F, Panzeri C, Renieri A, Comi GP, Turconi AC, Bresolin N, Bassi MT (2008) A clinical, genetic, and biochemical characterization of SPG7 mutations in a large cohort of patients with hereditary spastic paraplegia. Hum Mutat 29:522–531, doi:10.1002/humu.20682

    Article  CAS  PubMed  Google Scholar 

  19. Stevanin G, Azzedine H, Denora P, Boukhris A, Tazir M, Lossos A, Rosa AL, Lerer I, Hamri A, Alegria P, Loureiro J, Tada M, Hannequin D, Anheim M, Goizet C, Gonzalez-Martinez V, Le Ber I, Forlani S, Iwabuchi K, Meiner V, Uyanik G, Erichsen AK, Feki I, Pasquier F, Belarbi S, Cruz VT, Depienne C, Truchetto J, Garrigues G, Tallaksen C, Tranchant C, Nishizawa M, Vale J, Coutinho P, Santorelli FM, Mhiri C, Brice A, Durr A (2008) Mutations in SPG11 are frequent in autosomal recessive spastic paraplegia with thin corpus callosum, cognitive decline and lower motor neuron degeneration. Brain 131:772–784, doi:10.1093/brain/awm293

    Article  PubMed  Google Scholar 

  20. Depienne C, Fedirko E, Forlani S, Cazeneuve C, Ribai P, Feki I, Tallaksen C, Nguyen K, Stankoff B, Ruberg M, Stevanin G, Durr A, Brice A (2007) Exon deletions of SPG4 are a frequent cause of hereditary spastic paraplegia. J Med Genet 44:281–284, doi:10.1136/jmg.2006.046425

    Article  CAS  PubMed  Google Scholar 

  21. Hanein S, Durr A, Ribai P, Forlani S, Leutenegger AL, Nelson I, Babron MC, Elleuch N, Depienne C, Charon C, Brice A, Stevanin G (2007) A novel locus for autosomal dominant “uncomplicated” hereditary spastic paraplegia maps to chromosome 8p21.1-q13.3. Hum Genet 122:261–273, doi:10.1007/s00439-007-0396-1

    Article  CAS  PubMed  Google Scholar 

  22. Hewamadduma CA, Kirby J, Kershaw C, Martindale J, Dalton A, McDermott CJ, Shaw PJ (2008) HSP60 is a rare cause of hereditary spastic paraparesis, but may act as a genetic modifier. Neurology 70:1717–1718, doi:10.1212/01.wnl.0000311395.31081.70

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank the patients for participating and K. Stein for excellent technical assistance. This study was supported by the Deutsche Forschungsgemeinschaft (BE 4069/1-1 to C.B.) and the German Ministry for Education and Research (01GM0603 GeNeMove). All experiments reported in this study comply with the current laws of the country in which they were performed.

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Authors and Affiliations

  1. Sektion Klinische Neurogenetik, Hertie Institut für Klinische Hirnforschung, Tübingen, Germany

    Rebecca Schüle, Kathrin N. Karle & Ludger Schöls

  2. Institut für Klinische Chemie und Laboratoriumsdiagnostik, Universitätsklinikum Jena, Erlanger Allee 101, 07747, Jena, Germany

    Elisabeth Brandt, Christian A. Hübner, Thomas Deufel & Christian Beetz

  3. Department of Medical Genetics, St George’s University, London, UK

    Maria Tsaousidou & Andrew H. Crosby

  4. Klinik für Neurologie, Universitätsklinikum Schleswig-Holstein, Kiel, Germany

    Stephan Klebe

  5. Neurologische Klinik, Johannes-Gutenberg-Universität Mainz, Mainz, Germany

    Sven Klimpe

  6. Institut für Humangenetik und Zentrum für Medizinische Forschung, Medizinische Universität, Graz, Austria

    Michaela Auer-Grumbach

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  1. Rebecca Schüle
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Corresponding author

Correspondence to Christian Beetz.

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Supplementary Table 1

Previous genetic screens on primary cohort patients (DOC 35.0 KB)

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Schüle, R., Brandt, E., Karle, K.N. et al. Analysis of CYP7B1 in non-consanguineous cases of hereditary spastic paraplegia. Neurogenetics 10, 97–104 (2009). https://doi.org/10.1007/s10048-008-0158-9

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  • DOI: https://doi.org/10.1007/s10048-008-0158-9

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