title: Identification of the SPG15 gene, encoding spastizin, as a frequent cause of complicated autosomal-recessive spastic paraplegia, including Kjellin syndrome.
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.
authors.affiliation: 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.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Hanein
authors.forename: Elodie
authors.initials: E
authors.lastname: Martin
authors.forename: Amir
authors.initials: A
authors.lastname: Boukhris
authors.forename: Paula
authors.initials: P
authors.lastname: Byrne
authors.forename: Cyril
authors.initials: C
authors.lastname: Goizet
authors.forename: Abdelmadjid
authors.initials: A
authors.lastname: Hamri
authors.forename: Ali
authors.initials: A
authors.lastname: Benomar
authors.forename: Alexander
authors.initials: A
authors.lastname: Lossos
authors.forename: Paola
authors.initials: P
authors.lastname: Denora
authors.forename: José
authors.initials: J
authors.lastname: Fernandez
authors.forename: Nizar
authors.initials: N
authors.lastname: Elleuch
authors.forename: Sylvie
authors.initials: S
authors.lastname: Forlani
authors.forename: Alexandra
authors.initials: A
authors.lastname: Durr
authors.forename: Imed
authors.initials: I
authors.lastname: Feki
authors.forename: Michael
authors.initials: M
authors.lastname: Hutchinson
authors.forename: Filippo M
authors.initials: FM
authors.lastname: Santorelli
authors.forename: Chokri
authors.initials: C
authors.lastname: Mhiri
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.forename: Giovanni
authors.initials: G
authors.lastname: Stevanin
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001921:Brain / Q000378:metabolism; D002352:Carrier Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D002526:Cerebellar Diseases / Q000235:genetics*; D002648:Child; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics*; D004401:Dysarthria / Q000235:genetics*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D001523:Mental Disorders / Q000235:genetics*; D018908:Muscle Weakness / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D020161:Physical Chromosome Mapping; D051381:Rats; D012174:Retinitis Pigmentosa / Q000235:genetics*; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics*; D013577:Syndrome; D016335:Zinc Fingers / Q000235:genetics
chemical_list: D002352:Carrier Proteins; C528699:ZFYVE26 protein, human; C528700:ZFYVE26 protein, rat