title: Cathepsin F mutations cause Type B Kufs disease, an adult-onset neuronal ceroid lipofuscinosis.
abstract: Kufs disease, an adult-onset neuronal ceroid lipofuscinosis, is challenging to diagnose and genetically heterogeneous. Mutations in CLN6 were recently identified in recessive Kufs disease presenting as progressive myoclonus epilepsy (Type A), whereas the molecular basis of cases presenting with dementia and motor features (Type B) is unknown. We performed genome-wide linkage mapping of two families with recessive Type B Kufs disease and identified a single region on chromosome 11 to which both families showed linkage. Exome sequencing of five samples from the two families identified homozygous and compound heterozygous missense mutations in CTSF within this linkage region. We subsequently sequenced CTSF in 22 unrelated individuals with suspected recessive Kufs disease, and identified an additional patient with compound heterozygous mutations. CTSF encodes cathepsin F, a lysosomal cysteine protease, dysfunction of which is a highly plausible candidate mechanism for a storage disorder like ceroid lipofuscinosis. In silico modeling suggested the missense mutations would alter protein structure and function. Moreover, re-examination of a previously published mouse knockout of Ctsf shows that it recapitulates the light and electron-microscopic pathological features of Kufs disease. Although CTSF mutations account for a minority of cases of type B Kufs, CTSF screening should be considered in cases with early-onset dementia and may avoid the need for invasive biopsies.
authors.affiliation: Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne 3052, Australia.
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Smith
authors.forename: Hans-Henrik M
authors.initials: HH
authors.lastname: Dahl
authors.forename: Laura
authors.initials: L
authors.lastname: Canafoglia
authors.forename: Eva
authors.initials: E
authors.lastname: Andermann
authors.forename: John
authors.initials: J
authors.lastname: Damiano
authors.forename: Michela
authors.initials: M
authors.lastname: Morbin
authors.forename: Amalia C
authors.initials: AC
authors.lastname: Bruni
authors.forename: Giorgio
authors.initials: G
authors.lastname: Giaccone
authors.forename: Patrick
authors.initials: P
authors.lastname: Cossette
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.forename: Joachim
authors.initials: J
authors.lastname: Grötzinger
authors.forename: Michael
authors.initials: M
authors.lastname: Schwake
authors.forename: Frederick
authors.initials: F
authors.lastname: Andermann
authors.forename: John F
authors.initials: JF
authors.lastname: Staropoli
authors.forename: Katherine B
authors.initials: KB
authors.lastname: Sims
authors.forename: Sara E
authors.initials: SE
authors.lastname: Mole
authors.forename: Silvana
authors.initials: S
authors.lastname: Franceschetti
authors.forename: Noreen A
authors.initials: NA
authors.lastname: Alexander
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Cooper
authors.forename: Harold A
authors.initials: HA
authors.lastname: Chapman
authors.forename: Stirling
authors.initials: S
authors.lastname: Carpenter
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Berkovic
authors.forename: Melanie
authors.initials: M
authors.lastname: Bahlo
mesh_terms: D000328:Adult; D000818:Animals; D000870:Anterior Horn Cells / Q000473:pathology; D016022:Case-Control Studies; D056646:Cathepsin F / Q000235:genetics* / Q000378:metabolism; D002874:Chromosome Mapping; D003241:Consanguinity; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008126:Lod Score; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D008958:Models, Molecular; D020125:Mutation, Missense; D009472:Neuronal Ceroid-Lipofuscinoses / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017423:Sequence Analysis, RNA
chemical_list: C534090:CTSF protein, human; D056646:Cathepsin F