title: A mutation affecting the sodium/proton exchanger, SLC9A6, causes mental retardation with tau deposition.
abstract: We have studied a family with severe mental retardation characterized by the virtual absence of speech, autism spectrum disorder, epilepsy, late-onset ataxia, weakness and dystonia. Post-mortem examination of two males revealed widespread neuronal loss, with the most striking finding being neuronal and glial tau deposition in a pattern reminiscent of corticobasal degeneration. Electron microscopic examination of isolated tau filaments demonstrated paired helical filaments and ribbon-like structures. Biochemical studies of tau demonstrated a preponderance of 4R tau isoforms. The phenotype was linked to Xq26.3, and further analysis identified an in-frame 9 base pair deletion in the solute carrier family 9, isoform A6 (SLC9A6 gene), which encodes sodium/hydrogen exchanger-6 localized to endosomal vesicles. Sodium/hydrogen exchanger-6 is thought to participate in the targeting of intracellular vesicles and may be involved in recycling synaptic vesicles. The striking tau deposition in our subjects reveals a probable interaction between sodium/proton exchangers and cytoskeletal elements involved in vesicular transport, and raises the possibility that abnormalities of vesicular targeting may play an important role in more common disorders such as Alzheimer's disease and autism spectrum disorders.
authors.affiliation: Department of Neurology, Wayne State University School of Medicine, Detroit, MI 48201, USA. jgarbern@med.wayne.edu
authors.forename: James Y
authors.initials: JY
authors.lastname: Garbern
authors.forename: Manuela
authors.initials: M
authors.lastname: Neumann
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.forename: Gerald
authors.initials: G
authors.lastname: Feldman
authors.forename: Joy W
authors.initials: JW
authors.lastname: Norris
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Friez
authors.forename: Charles E
authors.initials: CE
authors.lastname: Schwartz
authors.forename: Roger
authors.initials: R
authors.lastname: Stevenson
authors.forename: Anders A F
authors.initials: AA
authors.lastname: Sima
mesh_terms: D001921:Brain / Q000378:metabolism / Q000473:pathology; D002675:Child, Preschool; D017353:Gene Deletion; D008040:Genetic Linkage; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism* / Q000523:psychology; D008297:Male; D008854:Microscopy, Electron; D008967:Molecular Biology / Q000379:methods; D009154:Mutation; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D020033:Protein Isoforms / Q000378:metabolism; D012720:Severity of Illness Index; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics*; D016875:tau Proteins / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D020033:Protein Isoforms; C445316:SLC9A6 protein, human; D017923:Sodium-Hydrogen Exchangers; D016875:tau Proteins
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