AJHG - Identification of the SPG15 Gene, Encoding Spastizin, as a Frequent Cause of Complicated Autosomal-Recessive Spastic Paraplegia, Including Kjellin Syndrome

Copyright © 2008 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 82, Issue 4, 992-1002, 03 April 2008

doi:10.1016/j.ajhg.2008.03.004

Article

Identification of the SPG15 Gene, Encoding Spastizin, as a Frequent Cause of Complicated Autosomal-Recessive Spastic Paraplegia, Including Kjellin Syndrome

Sylvain Hanein¹^,²^,¹⁴^,¹⁵, Elodie Martin¹^,²^,¹⁵, Amir Boukhris¹^,²^,³^,⁴, Paula Byrne⁵, Cyril Goizet¹^,²^,⁶, Abdelmadjid Hamri⁷, Ali Benomar⁸, Alexander Lossos⁹, Paola Denora¹^,²^,¹⁰, José Fernandez¹^,², Nizar Elleuch⁴, Sylvie Forlani¹^,², Alexandra Durr¹^,²^,³, Imed Feki⁴, Michael Hutchinson¹¹, Filippo M. Santorelli¹⁰, Chokri Mhiri⁴, Alexis Brice¹^,²^,³^,¹²^,¹³ and Giovanni Stevanin¹^,²^,³^,^,

¹ Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche (UMR) S679, Neurologie et Thérapeutique Expérimentale, Paris, F-75013 France
² Université Pierre et Marie Curie (UPMC), UMR S679, Paris F-75013, France
³ Assistance Publique-Hôpitaux de Paris (AP-HP), Groupe Hospitalier Pitié-Salpêtrière, Département de Génétique et Cytogénétique, Paris 75013, France
⁴ Service de Neurologie, Hôpital Universitaire Habib Bourguiba, 3029 Sfax, Tunisia
⁵ School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College, Belfield, Dublin 4, Ireland
⁶ Laboratoire de Génétique Humaine, Université Victor Segalen Bordeaux 2, Service de Génétique Médicale, Hôpital Pellegrin, Bordeaux 33076, France
⁷ Hôpital Benbadis, 25000 Constantine, Algeria
⁸ Départements de Neurologie B et Neurogénétique, Hôpital des Spécialités, BP 6402 Rabat, Morocco
⁹ Department of Neurology, Hadassah-Hebrew University Medical Center, POB 12000, Jerusalem, Israel
¹⁰ Unit of Molecular Medicine, IRCCS-Bambino Gesù Children's Hospital, 4-00165 Rome, Italy
¹¹ Department of Neurology, St Vincent's University Hospital, University College, Belfield, Dublin 4, Ireland
¹² AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Fédération de Neurologie, Paris 75013 France
¹³ Université Pierre et Marie Curie, Faculté de Médecine Pitié-Salpêtrière, Paris F-75013 France

Corresponding author

¹⁴ Present address: INSERM U781 et Service de Génétique, Hôpital des Enfants Malades, Paris 75743, France.

¹⁵ These authors contributed equally to this work.

Abstract

Hereditary spastic paraplegias (HSPs) are genetically and phenotypically heterogeneous disorders. Both “uncomplicated” and “complicated” forms have been described with various modes of inheritance. Sixteen loci for autosomal-recessive “complicated” HSP have been mapped. The SPG15 locus was first reported to account for a rare form of spastic paraplegia variably associated with mental impairment, pigmented maculopathy, dysarthria, cerebellar signs, and distal amyotrophy, sometimes designated as Kjellin syndrome. Here, we report the refinement of SPG15 to a 2.64 Mb genetic interval on chromosome 14q23.3-q24.2 and the identification of ZFYVE26, which encodes a zinc-finger protein with a FYVE domain that we named spastizin, as the cause of SPG15. Six different truncating mutations were found to segregate with the disease in eight families with a phenotype that included variable clinical features of Kjellin syndrome. ZFYVE26 mRNA was widely distributed in human tissues, as well as in rat embryos, suggesting a possible role of this gene during embryonic development. In the adult rodent brain, its expression profile closely resembled that of SPG11, another gene responsible for complicated HSP. In cultured cells, spastizin colocalized partially with markers of endoplasmic reticulum and endosomes, suggesting a role in intracellular trafficking.

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Response to Martignoni et al.

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Identification of the SPG15 Gene, Encoding Spastizin, as a Frequent Cause of Complicated Autosomal-Recessive Spastic Paraplegia, Including Kjellin Syndrome

Article Information

PubMed

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