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2017 BDSRA Storch and Danyukova CLN7
1. CLN7
disease
Using mouse models to understand CLN7 disease
PI: PD Dr. Stephan Storch, Dr. Tatyana Danyukova, cand. med. Khandsuren Ariunbat
Children’s Hospital, Section Biochemistry, University Medical Center Hamburg-Eppendorf, Germany
Financial support from the German Research Foundation (DFG), the Research Training Group 1459 (GRK1459), the
Batten Disease Support and Research Association (BDSRA) and the European Union (BATCure) is acknowledged.
This project has received funding from the European Union's Horizon 2020 research and innovation programme under
grant agreement No 666918 (www.batcure.eu).
Contact: Phone +49 40 7410 5 1967, E-mail storch@uke.de
www.uke.de/kliniken-institute/kliniken/kinder-und-jugendmedizin/forschung/sektion-biochemie/index.html
Retinal degeneration in 4-months-old Cln7 KO mice.
The thicknes of the outer nuclear layer (onl, blue), where
photoreceptors are located, is reduced in mice lacking Cln7
(Cln7 KO). GFAP-positive astroglial cells (red) in the
ganglion cell layer (gcl) start to proliferate. On the left an
age-matched wild type retina is shown for comparison.
Phenotype of the novel Cln7 knockout (KO) mouse model
• Photoreceptor loss and neuroinflammation in the retina by 1 month of age
• Lysosomal storage starting by 3 months of age in the brain
• Neuroinflammation starting by 5 months of age in the brain
• Hind limb clasping phenotype by 8 months of age
• Neurodegeneration in the brain late in disease
Conclusion
• Our novel mouse model recapitulates key features of
human CLN7 disease
• Loss of Cln7 in mice leads to lysosomal dysfunction in the
brain and the retina
• Multiple soluble lysosomal proteins are dysregulated in the
CLN7 mouse model
• A hypomorphic CLN7 mouse model and the presence of
adult patients with macular dystrophy lacking NCL
symptoms suggest that residual activity of CLN7 may
retard disease progression
• Retina is a good model to study the efficacy of novel
therapies due to an early onset, rapidly progressing
photoreceptor loss
• CLN7 disease, variant late-infantile phenotype is caused by mutations
in the MFSD8/CLN7 gene
• more than 35 mutations in MFSD8/CLN7 have been identified in CLN7
patients with variant late infantile phenotype
• MFSD8/CLN7 encodes a lysosomal membrane protein of unknown
function
Aim of the studies
Analysis of CLN7 function and test of experimental
therapies using a novel knockout (KO) mouse model for
CLN7 disease
Recent publications:
Damme, M, Brandenstein, L, Fehr, S, Jankowiak, A, Bartsch, U,
Hermans-Borgmeyer, I, Storch, S (2014) Gene disruption of Mfsd8 in
mice provides the first animal model for CLN7 disease. Neurobio. Dis.
65:12-24.
Brandenstein L, Schweizer M, Sedlacik J, Fiehler J, Storch S. (2016)
Lysosomal dysfunction and impaired autophagy in a novel mouse model
deficient for the lysosomal membrane protein Cln7. Hum. Mol. Genet.
25:777-791.
Jankowiak W, Brandenstein L, Dulz S, Hagel C, Storch S, Bartsch U.
(2016) Retinal degeneration in mice deficient in the lysosomal membrane
protein CLN7. Invest. Ophthalmol. Vis. Sci. 57: 4989-4998.
Presence of storage material (brown) in the kidney,
heart and liver of Cln7 KO mice.