Identification of the SPG15 gene, encoding spastizin, as a frequent cause of complicated autosomal-recessive spastic paraplegia, including Kjellin syndrome |
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Authors: | Hanein Sylvain Martin Elodie Boukhris Amir Byrne Paula Goizet Cyril Hamri Abdelmadjid Benomar Ali Lossos Alexander Denora Paola Fernandez José Elleuch Nizar Forlani Sylvie Durr Alexandra Feki Imed Hutchinson Michael Santorelli Filippo M Mhiri Chokri Brice Alexis Stevanin Giovanni |
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Affiliation: | 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 |
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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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