Identification of the SPG15 gene, encoding spastizin, as a frequent cause of complicated autosomal-recessive spastic paraplegia, including Kjellin syndrome.
The American Journal of Human Genetics. 2008-04-01; 82(4): 992-1002
DOI: 10.1016/j.ajhg.2008.03.004
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Hanein S(1), Martin E, Boukhris A, Byrne P, Goizet C, Hamri A, Benomar A, Lossos
A, Denora P, Fernandez J, Elleuch N, Forlani S, Durr A, Feki I, Hutchinson M,
Santorelli FM, Mhiri C, Brice A, Stevanin G.
Author information:
(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.
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.