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

Sylvain Hanein, Elodie Martin, Amir Boukhris, Paula Byrne, Cyril Goizet, Abdelmadjid Hamri, Ali Benomar, Alexander Lossos, Paola Denora, José Fernandez, Nizar Elleuch, Sylvie Forlani, Alexandra Durr, Imed Feki, Michael Hutchinson, Filippo M. Santorelli, Chokri Mhiri, Alexis Brice, Giovanni Stevanin

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)992-1002
Number of pages11
JournalAmerican Journal of Human Genetics
Volume82
Issue number4
DOIs
Publication statusPublished - Apr 11 2008

ASJC Scopus subject areas

  • Genetics

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