Skip to main content

Advertisement

SpringerLink
Log in

A novel locus for autosomal dominant “uncomplicated” hereditary spastic paraplegia maps to chromosome 8p21.1-q13.3

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

Hereditary spastic paraplegias (HSPs) are genetically and phenotypically heterogeneous. Both “uncomplicated” and “complicated” forms have been described, with autosomal dominant, autosomal recessive, and X-linked inheritance. Hitherto, ten autosomal dominant “uncomplicated” HSP (ADHSP) loci have been mapped. Here, we report linkage of ADHSP with markers of the 8p21.1-q13.3 chromosomal region in a large French family, including 29 examined at-risk individuals. The age at onset varied from 8 to 60 years with a mean of 31.6 ± 16.4 years. Multipoint and two-point LOD-score calculations as well as haplotype reconstruction in this region gave support to the location of this novel ADHSP locus (SPG37) in a 43.5 cM genetic interval flanked by loci D8S1839 and D8S1795. The region was shared by all definitely (n = 13), probably (n = 3) and possibly (n = 2) affected patients with a maximum LOD score of 4.20 at the D8S601 locus. Two candidate genes, encoding the kinesin family member 13B and neuregulin 1 (isoforms SMDF and GFF2), were screened for mutations, but no disease-causing alterations were identified. Interestingly, another region, on chromosome 10q22.3-23.31, was found to segregate in all affected patients (but not in probably or possibly affected subjects) and in a high proportion of healthy at risk individuals, suggesting that this locus might act as a modifier of the phenotype.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Al-Yahyaee S, Al-Gazali LI, De Jonghe P, Al-Barwany H, Al-Kindi M, De Vriendt E, Chand P, Koul R, Jacob PC, Gururaj A, Sztriha L, Parrado A, Van Broeckhoven C, Bayoumi RA (2006) A novel locus for hereditary spastic paraplegia with thin corpus callosum and epilepsy. Neurology 66:1230–1234

    Article  PubMed  CAS  Google Scholar 

  • Behan WM, Maia M (1974) Strumpell’s familial spastic paraplegia: genetics and neuropathology. J Neurol Neurosurg Psychiatry 37:8–20

    PubMed  CAS  Google Scholar 

  • Bouslam N, Benomar A, Azzedine H, Bouhouche A, Namekawa M, Klebe S, Charon C, Durr A, Ruberg M, Brice A, Yahyaoui M, Stevanin G (2005) Mapping of a new form of pure autosomal recessive spastic paraplegia (SPG28). Ann Neurol 57:567–571

    Article  PubMed  CAS  Google Scholar 

  • Cottingham RW Jr, Idury RM, Schaffer AA (1993) Faster sequential genetic linkage computations. Am J Hum Genet 53:252–263

    PubMed  Google Scholar 

  • D’Amico A, Tessa A, Sabino A, Bertini E, Santorelli FM, Servidei S (2004) Incomplete penetrance in an SPG3A-linked family with a new mutation in the atlastin gene. Neurology 62:2138–2139

    PubMed  CAS  Google Scholar 

  • De Jonghe P, Krols L, Michalik A, Hazan J, Smeyers G, Lofgren A, Weissenbach J, Martin JJ, Van Broeckhoven C (1996) Pure familial spastic paraplegia: clinical and genetic analysis of nine belgian pedigrees. Eur J Hum Genet 4:260–266

    PubMed  Google Scholar 

  • den Hollander AI, Koenekoop RK, Yzer S, Lopez I, Arends ML, Voesenek KE, Zonneveld MN, Strom TM, Meitinger T, Brunner HG, Hoyng CB, van den Born LI, Rohrschneider K, Cremers FP (2006) Mutations in the CEP290 (NPHP6) gene are a frequent cause of leber congenital amaurosis. Am J Hum Genet 79:556–561

    Article  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Dürr A, Brice A (2000) Clinical and genetic aspects of spinocerebellar degeneration. Curr Opin Neurol 13:407–413

    Article  PubMed  Google Scholar 

  • Dürr A, Brice A, Serdaru M, Rancurel G, Derouesne C, Lyon-Caen O, Agid Y, Fontaine B (1994) The phenotype of “pure” autosomal dominant spastic paraplegia. Neurology 44:1274–1277

    PubMed  Google Scholar 

  • Dürr A, Camuzat A, Colin E, Tallaksen C, Hannequin D, Coutinho P, Fontaine B, Rossi A, Gil R, Rousselle C, Ruberg M, Stevanin G, Brice A (2004) Atlastin1 mutations are frequent in young-onset autosomal dominant spastic paraplegia. Arch Neurol 61:1867–1872

    Article  PubMed  Google Scholar 

  • Filla A, De Michele G, Marconi R, Bucci L, Carillo C, Castellano AE, Iorio L, Kniahynicki C, Rossi F, Campanella G (1992) Prevalence of hereditary ataxias and spastic paraplegias in molise, a region of italy. J Neurol 239:351–353

    Article  PubMed  CAS  Google Scholar 

  • Fink JK (2006) Hereditary spastic paraplegia. Curr Neurol Neurosci Rep 6:65–76

    Article  PubMed  CAS  Google Scholar 

  • 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, Dürr A, Hazan J (2000) Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia. Hum Mol Genet 9:637–644

    Article  PubMed  CAS  Google Scholar 

  • Fontaine B, Davoine CS, Dürr A, Paternotte C, Feki I, Weissenbach J, Hazan J, Brice A (2000) A new locus for autosomal dominant pure spastic paraplegia, on chromosome 2q24-q34. Am J Hum Genet 66:702–707

    Article  PubMed  CAS  Google Scholar 

  • Fortini D, Cricchi F, Di Fabio R, Damiano M, Comanducci G, Benedetti L, Valoppi M, Grieco GS, D’Eugenio O, Celato A, Santorelli F, Casali C, Amabile GA, Pierelli F (2003) Current insights into familial spastic paraparesis: new advances in an old disease. Funct Neurol 18:43–49

    PubMed  Google Scholar 

  • Gerber S, Perrault I, Hanein S, Barbet F, Ducroq D, Ghazi I, Martin-Coignard D, Leowski C, Homfray T, Dufier JL, Munnich A, Kaplan J, Rozet JM (2001) Complete exon-intron structure of the RPGR-interacting protein (RPGRIP1) gene allows the identification of mutations underlying leber congenital amaurosis. Eur J Hum Genet 9:561–571

    Article  PubMed  CAS  Google Scholar 

  • Gerber S, Perrault I, Hanein S, Shalev S, Zlotogora J, Barbet F, Ducroq D, Dufier J, Munnich A, Rozet J, Kaplan J (2002) A novel mutation disrupting the cytoplasmic domain of CRB1 in a large consanguineous family of palestinian origin affected with leber congenital amaurosis. Ophthalmic Genet 23:225–235

    Article  PubMed  Google Scholar 

  • Hanada T, Lin L, Tibaldi EV, Reinherz EL, Chishti AH (2000) GAKIN, a novel kinesin-like protein associates with the human homologue of the drosophila discs large tumor suppressor in T lymphocytes. J Biol Chem 275:28774–28784

    Article  PubMed  CAS  Google Scholar 

  • Harding AE (1983) Classification of the hereditary ataxias and paraplegias. Lancet 1(8334):1151–1155

    Article  PubMed  CAS  Google Scholar 

  • Harding AE (1981) Hereditary “pure” spastic paraplegia: a clinical and genetic study of 22 families. J Neurol Neurosurg Psychiatry 44:871–883

    Article  PubMed  CAS  Google Scholar 

  • Hedera P, Rainier S, Alvarado D, Zhao X, Williamson J, Otterud B, Leppert M, Fink JK (1999) Novel locus for autosomal dominant hereditary spastic paraplegia, on chromosome 8q. Am J Hum Genet 64:563–569

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Hodgkinson CA, Bohlega S, Abu-Amero SN, Cupler E, Kambouris M, Meyer BF, Bharucha VA (2002) A novel form of autosomal recessive “pure” hereditary spastic paraplegia maps to chromosome 13q14. Neurology 59:1905–1909

    Article  PubMed  CAS  Google Scholar 

  • Lathrop GM, Ott J (1990) Analysis of complex diseases under oligogenic models and intrafamilial heterogeneity by the LINKAGE programs. Am J Hum Genet Suppl 47:A188

    Google Scholar 

  • Mannan AU, Krawen P, Sauter SM, Boehm J, Chronowska A, Paulus W, Neesen J, Engel W (2006) ZFYVE27 (SPG33), a novel spastin-binding protein, is mutated in hereditary spastic paraplegia. Am J Hum Genet 79(2):351–357

    Article  PubMed  CAS  Google Scholar 

  • Meijer IA, Cossette P, Roussel J, Benard M, Toupin S, Rouleau GA (2004) A novel locus for pure recessive hereditary spastic paraplegia maps to 10q22.1–10q24.1. Ann Neurol 56:579–82

    Article  PubMed  CAS  Google Scholar 

  • Meyer D, Yamaai T, Garratt A, Riethmacher-Sonnenberg E, Kane D, Theill LE, Birchmeier C (1997) Isoform-specific expression and function of neuregulin. Development 124:3575–3586

    PubMed  CAS  Google Scholar 

  • Namekawa M, Ribai P, Nelson I, Forlani S, Fellmann F, Goizet C, Depienne C, Stevanin G, Ruberg M, Durr A, Brice A (2006) SPG3A is the most frequent cause of hereditary spastic paraplegia with onset before age 10 years. Neurology 66:112–114

    Article  PubMed  CAS  Google Scholar 

  • Nielsen JE, Krabbe K, Jennum P, Koefoed P, Jensen LN, Fenger K, Eiberg H, Hasholt L, Werdelin L, Sorensen SA (1998) Autosomal dominant «uncomplicated» spastic paraplegia: a clinical, paraclinical, and genetic study. J Neurol Neurosurg Psychiatry 64:61–66

    PubMed  CAS  Google Scholar 

  • Okladnova O, Syagailo YV, Mossner R, Riederer P, Lesch KP (1998) Regulation of PAX-6 gene transcription: Alternate promoter usage in human brain. Brain Res Mol Brain Res 60:177–192

    Article  PubMed  CAS  Google Scholar 

  • Polo JM, Calleja J, Combarros O, Berciano J (1993) Hereditary “uncomplicated” spastic paraplegia: a study of nine families. J Neurol Neurosurg Psychiatry 56:175–181

    PubMed  CAS  Google Scholar 

  • Polo JM, Calleja J, Combarros O, Berciano J (1991) Hereditary ataxias and paraplegias in cantabria, spain. an epidemiological and clinical study. Brain 114(Pt 2):855–866

    Article  PubMed  Google Scholar 

  • Reid E, Dearlove AM, Osborn O, Rogers MT, Rubinsztein DC (2000) A locus for autosomal dominant “pure” hereditary spastic paraplegia maps to chromosome 19q13. Am J Hum Genet 66:728–732

    Article  PubMed  CAS  Google Scholar 

  • Reid E, Dearlove AM, Rhodes M, Rubinsztein DC (1999) A new locus for autosomal dominant “pure” hereditary spastic paraplegia mapping to chromosome 12q13, and evidence for further genetic heterogeneity. Am J Hum Genet 65:757–763

    Article  PubMed  CAS  Google Scholar 

  • Reid E, Kloos M, Ashley-Koch A, Hughes L, Bevan S, Svenson IK, Graham FL, Gaskell PC, Dearlove A, Pericak-Vance MA, Rubinsztein DC, Marchuk DA (2002) A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10). Am J Hum Genet 71:1189–1194

    Article  PubMed  CAS  Google Scholar 

  • Ribai P, Stevanin G, Bouslam N, Pontier B, Nelson I, Fontaine B, Dussert C, Charon C, Durr A, Brice A (2006) A new phenotype linked to SPG27 and refinement of the critical region on chromosome. J Neurol 253:714–9

    Article  PubMed  Google Scholar 

  • Sander T, Syagailo Y, Samochowiec J, Okladnova O, Lesch KP, Janz D (1999) Association analysis of a regulatory promoter polymorphism of the PAX-6 gene with idiopathic generalized epilepsy. Epilepsy Res 36:61–67

    Article  PubMed  CAS  Google Scholar 

  • Silberstein M, Tzemach A, Dovgolevsky N, Fishelson M, Schuster A, Geiger D (2006) Online system for faster multipoint linkage analysis via parallel execution on thousands of personal computers. Am J Hum Genet 78:922–935

    Article  PubMed  CAS  Google Scholar 

  • Steinmuller R, Lantigua-Cruz A, Garcia-Garcia R, Kostrzewa M, Steinberger D, Muller U (1997) Evidence of a third locus in X-linked recessive spastic paraplegia. Hum Genet 100:287–289

    Article  PubMed  CAS  Google Scholar 

  • Santorelli FM, Patrono C, Fortini D, Tessa A, Comanducci G, Bertini E, Pierallini A, Amabile GA, Casali C (2000) Intrafamilial variability in hereditary spastic paraplegia associated with an SPG4 gene mutation. Neurology 55:702–705

    PubMed  CAS  Google Scholar 

  • Stevanin G, Santorelli FM, Azzedine H, Coutinho P, Chomilier J, Denora PS, Martin E, Ouvrard-Hernandez AM, Tessa A, Bouslam N, Lossos A, Charles P, Loureiro JL, Elleuch N, Confavreux C, Cruz VT, Ruberg M, Leguern E, Grid D, Tazir M, Fontaine B, Filla A, Bertini E, Durr A, Brice A (2007) Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum. Nat Genet 39:366–372

    Article  PubMed  CAS  Google Scholar 

  • Svenson IK, Ashley-Koch AE, Gaskell PC, Riney TJ, Cumming WJ, Kingston HM, Hogan EL, Boustany RM, Vance JM, Nance MA, Pericak-Vance MA, Marchuk DA (2001) Identification and expression analysis of spastin gene mutations in hereditary spastic paraplegia. Am J Hum Genet 68:1077–1085

    Article  PubMed  CAS  Google Scholar 

  • Tallaksen CM, Durr A, Brice A (2001) Recent advances in hereditary spastic paraplegia. Curr Opin Neurol 14:457–463

    Article  PubMed  CAS  Google Scholar 

  • Valdmanis PN, Meijer IA, Reynolds A, Lei A, MacLeod P, Schlesinger D, Zatz M, Reid E, Dion PA, Drapeau P, Rouleau GA (2007) Mutations in the KIAA0196 gene at the SPG8 locus cause hereditary spastic paraplegia. Am J Hum Genet 80(1):152–161

    Article  PubMed  CAS  Google Scholar 

  • Waggoner SA, Liebhaber SA (2003) Regulation of alpha-globin mRNA stability. Exp Biol Med (Maywood) 228:387–395

    CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Zheng JB, Zhou YH, Maity T, Liao WS, Saunders GF (2001) Activation of the human PAX6 gene through the exon 1 enhancer by transcription factors SEF and Sp1. Nucleic Acids Res 29:4070–4078

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Elodie Denis, Estelle Fedirko, Claire-Sophie Rime-Davoine and Drs B. Fontaine, C. Paternotte, E. Reid and J. Hazan for their help and Drs C. Goizet and S. Cogilnicean for clinical examinations. We are grateful to N. Barton and Drs M. Ruberg and J.M. Rozet for critical reading of the manuscript. This study was supported financially by the VERUM foundation (Germany) and the Programme Hospitalier de Recherche Clinique (France).

Author information

Authors and Affiliations

  1. INSERM, Unit 679, 47 Bd de l’Hôpital, 75013, Paris, France

    Sylvain Hanein, Alexandra Dürr, Pascale Ribai, Sylvie Forlani, Isabelle Nelson, Nizar Elleuch, Christel Depienne, Alexis Brice & Giovanni Stevanin

  2. Institut Fédératif de Recherche en Neurosciences (IFR70), Groupe Hospitalier Pitié-Salpêtrière, Université Pierre et Marie Curie, Paris 6, UMR S679, Paris, France

    Sylvain Hanein, Alexandra Dürr, Pascale Ribai, Sylvie Forlani, Isabelle Nelson, Nizar Elleuch, Christel Depienne, Alexis Brice & Giovanni Stevanin

  3. Département de Génétique et Cytogénétique, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France

    Alexandra Dürr, Christel Depienne, Alexis Brice & Giovanni Stevanin

  4. INSERM, U535, Villejuif, 94817, France

    Anne-Louise Leutenegger & Marie-Claude Babron

  5. Univ. Paris-Sud, IFR69, UMR-S535, Villejuif, 94817, France

    Anne-Louise Leutenegger & Marie-Claude Babron

  6. Centre National de Génotypage, Evry, France

    Céline Charon

  7. Fédération de Neurologie, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France

    Alexis Brice

  8. Faculté de Médecine, Groupe Hospitalier Pitié-Salpêtrière, Université Pierre et Marie Curie, Paris 6, Paris, France

    Alexis Brice

Authors
  1. Sylvain Hanein
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alexandra Dürr
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pascale Ribai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sylvie Forlani
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anne-Louise Leutenegger
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Isabelle Nelson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Marie-Claude Babron
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nizar Elleuch
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Christel Depienne
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Céline Charon
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Alexis Brice
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Giovanni Stevanin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Alexandra Dürr or Giovanni Stevanin.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material: Use of TLinkage (DOC 25 kb).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hanein, S., Dürr, A., Ribai, P. et al. A novel locus for autosomal dominant “uncomplicated” hereditary spastic paraplegia maps to chromosome 8p21.1-q13.3. Hum Genet 122, 261–273 (2007). https://doi.org/10.1007/s00439-007-0396-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-007-0396-1

Keywords

Search

Navigation