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. 2013 Apr 1;22(7):1417-23.
doi: 10.1093/hmg/dds558. Epub 2013 Jan 7.

Cathepsin F mutations cause Type B Kufs disease, an adult-onset neuronal ceroid lipofuscinosis

Katherine R Smith  1 , Hans-Henrik M Dahl, Laura Canafoglia, Eva Andermann, John Damiano, Michela Morbin, Amalia C Bruni, Giorgio Giaccone, Patrick Cossette, Paul Saftig, Joachim Grötzinger, Michael Schwake, Frederick Andermann, John F Staropoli, Katherine B Sims, Sara E Mole, Silvana Franceschetti, Noreen A Alexander, Jonathan D Cooper, Harold A Chapman, Stirling Carpenter, Samuel F Berkovic, Melanie Bahlo
Affiliations

Cathepsin F mutations cause Type B Kufs disease, an adult-onset neuronal ceroid lipofuscinosis

Katherine R Smith et al. Hum Mol Genet. .

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.

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Figures

Figure 1.
Figure 1.
Kufs disease pedigrees and CTSF mutational status. Individuals from Ku4 and Ku10 whose genotypes were used for linkage analysis are indicated with a hash sign. Individuals whose exomes were sequenced are indicated with an asterisk.
Figure 2.
Figure 2.
Brain pathology of the proband (II-3) of family Ku4. Light microscopy (A and B: at same magnification; bar = 25 µm) shows cortical neurons containing abundant storage material that is autofluorescent (A, yellow) and immunoreactive for ubiquitin (B, brown reaction product; anti-ubiquitin polyclonal antibody, 1:1000; DakoCytomation). Note anti-ubiquitin immunolabeling extending to swollen proximal axons, a feature characteristic of NCL. Electron microscopy (C; bar = 100 nm) shows diagnostic fingerprint profiles in neurons.
Figure 3.
Figure 3.
Overlap of linkage peaks obtained by linkage analysis of Ku10 and Ku4. Genome-wide LOD scores were obtained by linkage analysis of the Ku4 and Ku10 families under a fully penetrant recessive genetic model.
Figure 4.
Figure 4.
A ribbon representation of the cathepsin F structure (7). Side chains of the catalytic triad (C295, H431 and N451) are depicted. Substrate binding and recognition is mediated by the loop preceding the catalytic C295 (blue). Lysine 287 (K287) is part of this loop and forms an ion pair with glutamic acid 320 (E320). This interaction keeps the loop (blue) in its conformation. The mutated residue Q321 (p.Gln321Arg) is buried under a loop (green). Changing the electrostatic environment by the Gln to Arg mutation at position 321 may lead to disruption of the ion pair E320–K287 and induction of a conformational change in the binding loop that renders substrate binding and lowers the catalytic efficiency.
Figure 5.
Figure 5.
This electron micrograph from an anterior horn cell of a Ctsf knockout mouse shows part of an intracellular membrane-bound organelle filled with rectilinear complex. Pentalaminar structures are present.
See this image and copyright information in PMC

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