A new locus (SPG46) maps to 9p21.2-q21.12 in a Tunisian family with a complicated autosomal recessive hereditary spastic paraplegia with mental impairment and thin corpus callosum (original) (raw)

Abstract

Hereditary spastic paraplegia (HSP) with thin corpus callosum (TCC) and mental impairment is a frequent subtype of complicated HSP, often inherited as an autosomal recessive (AR) trait. It is clear from molecular genetic analyses that there are several underlying causes of this syndrome, with at least six genetic loci identified to date. However, SPG11 and SPG15 are the two major genes for this entity. To map the responsible gene in a large AR-HSP-TCC family of Tunisian origin, we investigated a consanguineous family with a diagnosis of AR-HSP-TCC excluded for linkage to the SPG7, SPG11, SPG15, SPG18, SPG21, and SPG32 loci. A genome-wide scan was undertaken using 6,090 SNP markers covering all chromosomes. The phenotypic presentation in five patients was suggestive of a complex HSP that associated an early-onset spastic paraplegia with mild handicap, mental deterioration, congenital cataract, cerebellar signs, and TCC. The genome-wide search identified a single candidate region on chromosome 9, exceeding the LOD score threshold of +3. Fine mapping using additional markers narrowed the candidate region to a 45.1-Mb interval (15.4 cM). Mutations in three candidate genes were excluded. The mapping of a novel AR-HSP-TCC locus further demonstrates the extensive genetic heterogeneity of this condition. We propose that testing for this locus should be performed, after exclusion of mutations in SPG11 and SPG15 genes, in AR-HSP-TCC families, especially when cerebellar ataxia and cataract are present.

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Acknowledgments

The authors thank their family members for their participation. They also thank Dr. Nick Barton and Dr. Cyril Goizet for critical reading of the manuscript.

This work was financially supported by the French–Tunisian Cooperation Project (to A. Br. and C. M.) led by INSERM (France) and DGRSRT (Tunisia), the VERUM Foundation (to A. Br.), the French Agency for Research (ANR) (to G. S. and A. Br., SPAX and SPG11 projects), and the European Community with the ANR (to A. Br., Eurospa project). A. Bou. received a fellowship from the Association Strümpell-Lorrain (ASL, France).

The authors report no disclosures except funding sources from national research agencies as indicated earlier.

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Authors and Affiliations

1. Department of Neurology, Habib Bourguiba University Hospital, Sfax, Tunisia
   Amir Boukhris, Imed Feki, Nizar Elleuch, Mohamed Imed Miladi & Chokri Mhiri
2. Faculté de Médecine de Sfax, Sfax, Tunisia
   Amir Boukhris, Imed Feki, Nizar Elleuch, Mohamed Imed Miladi & Chokri Mhiri
3. INSERM, U975 (formerly U679), 75013, Paris, France
   Amir Boukhris, Jérémy Truchetto, Emeline Mundwiller, Nadia Jezequel, Alexis Brice & Giovanni Stevanin
4. Université Pierre et Marie Curie-Paris 6, Unité Mixte de Recherche S975, CNRS 7225, Centre de Recherche de l’Institut du Cerveau et de la Moelle Epinière, Groupe Hospitalier Universitaire Pitié-Salpêtrière, 75013, Paris, France
   Amir Boukhris, Jérémy Truchetto, Emeline Mundwiller, Nadia Jezequel, Alexis Brice & Giovanni Stevanin
5. Centre National de Génotypage, Evry, France
   Anne Boland-Augé & Diana Zelenika
6. AP-HP, Pitié-Salpêtrière Hospital, Department of Genetics and Cytogenetics, Paris, France
   Amir Boukhris, Alexis Brice & Giovanni Stevanin
7. Ecole Pratique des Hautes Etudes, Paris, France
   Giovanni Stevanin
8. Service de Neurologie, Hôpital Habib Bourguiba, 3029, Sfax, Tunisia
   Amir Boukhris

Authors

1. Amir Boukhris
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2. Imed Feki
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3. Nizar Elleuch
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4. Mohamed Imed Miladi
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5. Anne Boland-Augé
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6. Jérémy Truchetto
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7. Emeline Mundwiller
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8. Nadia Jezequel
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9. Diana Zelenika
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10. Chokri Mhiri
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11. Alexis Brice
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12. Giovanni Stevanin
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Correspondence toAmir Boukhris.

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Boukhris, A., Feki, I., Elleuch, N. et al. A new locus (SPG46) maps to 9p21.2-q21.12 in a Tunisian family with a complicated autosomal recessive hereditary spastic paraplegia with mental impairment and thin corpus callosum.Neurogenetics 11, 441–448 (2010). https://doi.org/10.1007/s10048-010-0249-2

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• Received: 03 April 2010
• Accepted: 14 June 2010
• Published: 01 July 2010
• Issue Date: October 2010
• DOI: https://doi.org/10.1007/s10048-010-0249-2

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