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.