Gene disruption of Mfsd8 in mice provides the first animal model for CLN7 disease

Damme, Markus; Brandenstein, Laura; Fehr, Susanne; Jankowiak, Wanda; Bartsch, Udo; Schweizer, Michaela; Hermans‐Borgmeyer, Irm; Storch, Stephan

doi:10.1016/j.nbd.2014.01.003

Cited by 44 publications

(47 citation statements)

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“…11 However, precise information about the onset and progression of the retinal pathology, the affected retinal layers and retinal cell types, and the biochemical alterations associated with CLN7 disease, vLINCL phenotype, are largely missing. In the present study, we therefore performed a detailed analysis of the retinal phenotype of a novel Cln7 KO mouse that was generated by deleting Cln7/ Mfsd8 exon 2, resulting in the expression of a truncated, nonfunctional p.Glu23PhefsX16 protein.…”

Section: Discussionmentioning

confidence: 99%

“…18 A high susceptibility of the retina to CLN7 dysfunction is also suggested by the recent finding that a hypomorphic CLN7 mouse line showed a marked loss of photoreceptor cells, but no neurodegeneration in the brain even in animals as old as 10 months. 11 Furthermore, a recent study has identified compound heterozygous variants in CLN7/MFSD8 in two families presenting with autosomal recessive macular dystrophy with central cone involvement, but without the other neurologic symptoms characteristic for vLINCL, such as seizures, mental regression, or motor impairment. 23 Affected individuals were compound heterozygous for the missense mutation p.Glu336Gln predicted to have a mild effect on the protein and the severe nonsense mutation p.Glu381X or the severe frame-shift mutation p.Lys333LysfsX3.…”

Section: Discussionmentioning

confidence: 99%

“…11 In the present study, we performed a detailed analysis of the onset and progression of the retinal pathology in a novel Cln7 KO mouse model that lacks exon 2 of the murine Cln7/Mfsd8 gene and more closely recapitulates the neurologic phenotype observed in human patients with CLN7 with the vLINCL phenotype. 36 To analyze the impact of CLN7 deficiency on retinal morphology, we performed immunohistochemical analyses of glial fibrillary acidic protein (GFAP) expression in central retina sections from Cln7 KO and wild-type mice at different developmental ages.…”

Section: Retinal Degeneration and Reactive Astrogliosis And Microgliomentioning

confidence: 99%

“…[7][8][9] Proteomic and immunoblotting analyses using rat, human, or mouse tissues have identified CLN7 as an integral lysosomal membrane protein that is sorted to lysosomes via an N-terminal di-leucine motif. [10][11][12][13] CLN7 is cleaved twice by cysteine proteases in lysosomes. 14 Human CLN7/MFSD8 mRNA is ubiquitously expressed and rat Cln7/ Mfsd8 mRNA has been shown to be 6-fold and 12-fold more abundant in cultured neurons when compared with cultured astrocytes and microglial cells, respectively.…”

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confidence: 99%

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Retinal Degeneration in Mice Deficient in the Lysosomal Membrane Protein CLN7

Jankowiak

Brandenstein

Dulz

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Neuronal ceroid lipofuscinoses comprise a genetically heterogeneous group of mainly childhood-onset neurodegenerative lysosomal storage disorders. Progressive loss of vision is among the typical clinical symptoms of these fatal disorders. Here, we performed a detailed analysis of retinal degeneration in mice deficient in the lysosomal membrane protein CLN7, a novel animal model of CLN7 disease.METHODS. Immunohistochemical analyses of retinas at different ages were performed to qualitatively and quantitatively characterize retinal degeneration in CLN7-deficient mice. Storage material in mutant retinas was analyzed by electron microscopy, and expression levels of various lysosomal proteins were studied using immunohistochemistry, immunoblot analyses, and quantitative real-time PCR.RESULTS. We observed an early onset and rapidly progressing degeneration of photoreceptor cells in CLN7-deficient mice, resulting in the loss of more than 70% rod photoreceptors in 4-month-old animals. The number of cone photoreceptors was not detectably altered at this age. Loss of rod photoreceptors was accompanied by reactive astrogliosis and microgliosis. Immunohistochemical and immunoblot analyses revealed accumulation of subunit c of mitochondrial ATP synthase and saposin D in mutant retinas, and electron microscopic analyses demonstrated the presence of curvilinear bodies or fingerprint-like profiles in various cell types of CLN7-deficient retinas. We also found a marked dysregulation of various lysosomal proteins in mutant retinas. CONCLUSIONS.We conclude that the retina of CLN7-deficient mice represents a useful model to elucidate the pathomechanisms ultimately leading to neurodegeneration in CLN7 disease, and to evaluate the efficacy of strategies aimed at developing treatments for this fatal neurodegenerative lysosomal storage disorder.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Retinal Degeneration and Reactive Astrogliosis And Microgliomentioning

confidence: 99%

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confidence: 99%

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Retinal Degeneration in Mice Deficient in the Lysosomal Membrane Protein CLN7

Jankowiak

Brandenstein

Dulz

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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“…This may lead to downstream secondary consequences that have been described such as the accumulation of aggregate storage material in neuronal cells, 5,16,31,32 impaired autophagy, 33 and cell death, as well as accompanying inflammation that occurs both in the brains of MFSD8-deficient patients 31 and in the MFSD8-knockout dog 34 and mouse models. 33,35 All previously published MFSD8 mutation combinations associated with disease are listed at http://www.ucl.ac.uk/ncl/ and Alexa Fluor 568-conjugated secondary antibody (red) or Alexa Fluor 488-conjugated secondary antibody (green) and DAPI nuclear counterstain (blue) are shown. The secondary antibody alone or anti-MFSD8 preincubated with peptide were incubated with different serial sections as controls in the experiment.…”

Section: Figurementioning

confidence: 99%

Specific Alleles of CLN7/MFSD8, a Protein That Localizes to Photoreceptor Synaptic Terminals, Cause a Spectrum of Nonsyndromic Retinal Dystrophy

Khan¹,

El‐Asrag

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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Citation: Khan KN, El-Asrag ME, Ku CA, et al.; for NIHR BioResource-Rare Diseases and UK Inherited Retinal Disease Consortium. Specific alleles of CLN7/ MFSD8, a protein that localizes to photoreceptor synaptic terminals, cause a spectrum of nonsyndromic retinal dystrophy. Invest Ophthalmol Vis Sci. 2017;58:290658: -291458: . DOI:10.1167 PURPOSE. Recessive mutations in CLN7/MFSD8 usually cause variant late-infantile onset neuronal ceroid lipofuscinosis (vLINCL), a poorly understood neurodegenerative condition, though mutations may also cause nonsyndromic maculopathy. A series of 12 patients with nonsyndromic retinopathy due to novel CLN7/MFSD8 mutation combinations were investigated in this study. METHODS.Affected patients and their family members were recruited in ophthalmic clinics at each center where they were examined by retinal imaging and detailed electrophysiology. Whole exome or genome next generation sequencing was performed on genomic DNA from at least one affected family member. Immunofluorescence confocal microscopy of murine retina cross-sections were used to localize the protein. RESULTS.Compound heterozygous alleles were identified in six cases, one of which was always p.Glu336Gln. Such combinations resulted in isolated macular disease. Six further cases were homozygous for the variant p.Met454Thr, identified as a founder mutation of South Asian origin. Those patients had widespread generalized retinal disease, characterized by electroretinography as a rod-cone dystrophy with severe macular involvement. In addition, the photopic single flash electroretinograms demonstrated a reduced b-to a-wave amplitude ratio, suggesting dysfunction occurring after phototransduction. Immunohistology identified MFSD8 in the outer plexiform layer of the retina, a site rich in photoreceptor synapses.CONCLUSIONS. This study highlights a hierarchy of MFSD8 variant severity, predicting three consequences of mutation: (1) nonsyndromic localized maculopathy, (2) nonsyndromic widespread retinopathy, or (3) syndromic neurological disease. The data also shed light on the underlying pathogenesis by implicating the photoreceptor synaptic terminals as the major site of retinal disease.

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The Chihuahua dog: A new animal model for neuronal ceroid lipofuscinosis CLN7 disease?

Faller

Brás

Sharpe

et al. 2016

J of Neuroscience Research

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39Neuronal ceroid lipofuscinoses (NCL) are a group of incurable lysosomal storage 40 disorders characterized by neurodegeneration and accumulation of lipopigments 41 mainly within the neurons. We studied two littermate Chihuahua dogs presenting with 42 progressive signs of blindness, ataxia, pacing and cognitive impairment from the age 43 of one year old. Due to worsening of clinical signs, both dogs were euthanized at 44 SIGNIFICANCE STATEMENT 59NCL are a group of incurable lysosomal storage disorders unified by similar 60 histopathological changes. Although mutations in 13 genes coding for functionally 61 distinct proteins have been identified, the pathophysiology of these diseases is still 62 poorly understood. Naturally occurring large animal models have had an invaluable 63 contribution to better understand the pathophysiology and therapeutic options of some 64 forms of NCL. CLN7 is a poorly characterized form, and this could be due to a lack 65 of animal models that closely reproduce the human phenotype. We identified 66

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Gene disruption of Mfsd8 in mice provides the first animal model for CLN7 disease

Cited by 44 publications

References 46 publications

Retinal Degeneration in Mice Deficient in the Lysosomal Membrane Protein CLN7

Retinal Degeneration in Mice Deficient in the Lysosomal Membrane Protein CLN7

Specific Alleles of CLN7/MFSD8, a Protein That Localizes to Photoreceptor Synaptic Terminals, Cause a Spectrum of Nonsyndromic Retinal Dystrophy

The Chihuahua dog: A new animal model for neuronal ceroid lipofuscinosis CLN7 disease?

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