Mutations in MFSD8, Encoding a Lysosomal Membrane Protein, Are Associated with Nonsyndromic Autosomal Recessive Macular Dystrophy

Roosing, Susanne; Born, L. Ingeborgh van den; Sangermano, Riccardo; Banfi, Sandro; Koenekoop, Robert K.; Zonneveld-Vrieling, Marijke N.; Klaver, Caroline C.W.; Lith-Verhoeven, Janneke J.C. van; Cremers, Frans P.M.; Hollander, Anneke I. den; Hoyng, Carel B.

doi:10.1016/j.ophtha.2014.07.040

Cited by 62 publications

(55 citation statements)

References 56 publications

(53 reference statements)

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“…23 The combined observations suggest a residual activity of CLN7 in the hypomorphic CLN7 mouse line and in the patients with CLN7 with nonsyndromic macular dystrophy with central cone involvement that is sufficient to maintain the integrity of all tissues with the exception of the retina. Whereas retinal degeneration in patients carrying compound heterozygous variants in CLN7/MFS8D and presenting without the typical extraocular symptoms of vLINCL is characterized by an initial loss of cone photoreceptor cells, 23 retinal degeneration in Cln7 KO mice is characterized by a preferential degeneration of rod photoreceptor cells. More detailed information about the progression of retinal degeneration in patients with CLN7 with vLINCL phenotype are required to judge whether or not these apparently discrepant findings indicate speciesspecific differences in the impact of CLN7 dysfunction on retinal morphology.…”

Section: Discussionmentioning

confidence: 94%

“…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. 23 The combined observations suggest a residual activity of CLN7 in the hypomorphic CLN7 mouse line and in the patients with CLN7 with nonsyndromic macular dystrophy with central cone involvement that is sufficient to maintain the integrity of all tissues with the exception of the retina.…”

Section: Discussionmentioning

confidence: 99%

“…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. 23 The combined observations suggest a residual activity of CLN7 in the hypomorphic CLN7 mouse line and in the patients with CLN7 with nonsyndromic macular dystrophy with central cone involvement that is sufficient to maintain the integrity of all tissues with the exception of the retina. Whereas retinal degeneration in patients carrying compound heterozygous variants in CLN7/MFS8D and presenting without the typical extraocular symptoms of vLINCL is characterized by an initial loss of cone photoreceptor cells, 23 retinal degeneration in Cln7 KO mice is characterized by a preferential degeneration of rod photoreceptor cells.…”

Section: Discussionmentioning

confidence: 99%

“…18 Furthermore, compound heterozygous variants in CLN7/MFSD8 have been identified in patients presenting with autosomal recessive macular dystrophy with central cone involvement but lacking the characteristic hallmarks and severe neurologic symptoms of patients with CLN7 with the vLINCL phenotype (MIM 616170). 23 Of interest in the present context, visual impairment has been diagnosed in up to 90% of patients with CLN7 aged between 2 and 7 years, 18 and morphologic analyses of retinas from patients with CLN7 who are homozygous for the most common missense mutation p.Thr294Lys have demonstrated the presence of autofluorescent storage material, a marked loss of neurons in the ganglion cell layer and inner nuclear layer, and a complete loss of the photoreceptor cell layer. 22 For most NCL variants, transgenic or naturally occurring mouse models are available that replicate key features of human NCL diseases.…”

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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: 94%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

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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“…Recently, recessive mutations in MFSD8 have also been associated with nonsyndromic macular dystrophy in two families. 9 Retinal dysfunction in the absence of syndromic association had not previously been reported. Despite many advances in NCL research, the biological basis for neurodegeneration remains elusive.…”

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confidence: 92%

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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Detailed Clinical Phenotype and Molecular Genetic Findings in CLN3-Associated Isolated Retinal Degeneration

Hull

Arno

et al. 2017

JAMA Ophthalmol

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IMPORTANCE Mutations in genes traditionally associated with syndromic retinal disease are increasingly found to cause nonsyndromic inherited retinal degenerations. Mutations in CLN3 are classically associated with juvenile neuronal ceroid lipofuscinosis, a rare neurodegenerative disease with early retinal degeneration and progressive neurologic deterioration, but have recently also been identified in patients with nonsyndromic inherited retinal degenerations. To our knowledge, detailed clinical characterization of such cases has yet to be reported.OBJECTIVE To provide detailed clinical, electrophysiologic, structural, and molecular genetic findings in nonsyndromic inherited retinal degenerations associated with CLN3 mutations. DESIGN, SETTING, AND PARTICIPANTSA multi-institutional case series of 10 patients who presented with isolated nonsyndromic retinal disease and mutations in CLN3. Patient ages ranged from 16 to 70 years; duration of follow-up ranged from 3 to 29 years. MAIN OUTCOMES AND MEASURESLongitudinal clinical evaluation, including full ophthalmic examination, multimodal retinal imaging, perimetry, and electrophysiology. Molecular analyses were performed using whole-genome sequencing or whole-exome sequencing. Electron microscopy studies of peripheral lymphocytes and CLN3 transcript analysis with polymerase chain reaction amplification were performed in a subset of patients.RESULTS There were 7 females and 3 males in this case series, with a mean (range) age at last review of 37.1 (16-70) years. Of the 10 patients, 4 had a progressive late-onset rod-cone dystrophy, with a mean (range) age at onset of 29.7 (20-40) years, and 6 had an earlier onset rod-cone dystrophy, with a mean (range) age at onset of 12.1 (7-17) years. Ophthalmoscopic examination features included macular edema, mild intraretinal pigment migration, and widespread atrophy in advanced disease. Optical coherence tomography imaging demonstrated significant photoreceptor loss except in patients with late-onset disease who had a focal preservation of the ellipsoid zone and outer nuclear layer in the fovea. Electroretinography revealed a rod-cone pattern of dysfunction in 6 patients and were completely undetectable in 2 patients. Six novel CLN3 variants were identified in molecular analyses.CONCLUSIONS AND RELEVANCE This report describes detailed clinical, imaging, and genetic features of CLN3-associated nonsyndromic retinal degeneration. The age at onset and natural progression of retinal disease differs greatly between syndromic and nonsyndromic CLN3 disease, which may be associated with genotypic differences.

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Mutations in MFSD8, Encoding a Lysosomal Membrane Protein, Are Associated with Nonsyndromic Autosomal Recessive Macular Dystrophy

Cited by 62 publications

References 56 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

Detailed Clinical Phenotype and Molecular Genetic Findings in CLN3-Associated Isolated Retinal Degeneration

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