Clinico-pathological manifestations of variant late infantile neuronal ceroid lipofuscinosis (vLINCL) caused by a novel mutation in MFSD8 gene

Mandel, Hanna; Katsanelson, Ksenya Cohen; Khayat, Morad; Chervinsky, Ilana; Vladovski, Eugene; Iancu, T. C.; Indelman, Margarita; Horovitz, Yoseph; Sprecher, Eli; Shalev, Stavit A.; Spiegel, Ronen

doi:10.1016/j.ejmg.2014.09.004

Cited by 22 publications

(17 citation statements)

References 15 publications

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“…Even though the strength of this association is slightly above our threshold for statistical significance after multiple testing correction (P Bo nf < 0.05), we pursued this finding in follow-up studies for several reasons. First, prior studies have found that recessive pathogenic variants in MFSD8 cause late infantile neuronal ceroid lipofuscinosis (NCL) [2, 30, 40, 67], a childhood neurodegenerative lysosomal-storage disorder. Second, the link between MFSD8 and NCL is akin to observations with GRN, for which heterozygous pathogenic variants result in autosomal dominant FTLD and homozygous pathogenic variants cause NCL.…”

Section: Resultsmentioning

confidence: 99%

Rare variants in the neuronal ceroid lipofuscinosis gene MFSD8 are candidate risk factors for frontotemporal dementia

et al. 2018

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Pathogenic variation in MAPT, GRN, and C9ORF72 accounts for at most only half of frontotemporal lobar degeneration (FTLD) cases with a family history of neurological disease. This suggests additional variants and genes remain to be identified as risk factors for FTLD. We conducted a case-control genetic association study comparing pathologically diagnosed FTLD patients (n = 94) to cognitively normal older adults (n = 3,541), and found suggestive evidence that gene-wide aggregate rare variant burden in MFSD8 associates with FTLD risk. Because homozygous mutations in MFSD8 cause neuronal ceroid lipofuscinosis (NCL), similar to homozygous mutations in GRN, we assessed rare variants in MFSD8 for relevance to FTLD through experimental follow-up studies. Using post-mortem tissue from middle frontal gyrus (MFG) of patients with FTLD and controls, we identified increased MFSD8 protein levels in MFSD8 rare variant carriers relative to non-variant carrier patients with sporadic FTLD and healthy controls. We also observed increases in lysosomal and autophagy-related proteins in MFSD8 rare variant carrier and sporadic FTLD patients relative to controls. Immunohistochemical analysis revealed that MFSD8 was expressed in neurons and astrocytes across subjects, without clear evidence of abnormal localization in patients. Finally, in vitro studies identified marked disruption of lysosomal function in cells from MFSD8 rare variant carriers, and identified one rare variant that significantly increased the cell surface levels of MFSD8. Considering the growing evidence for altered autophagy in the pathogenesis of neurodegenerative disorders, our findings support a role of NCL genes in FTLD risk and suggest that MFSD8-associated lysosomal dysfunction may contribute to FTLD pathology.

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Section: Resultsmentioning

confidence: 99%

Rare variants in the neuronal ceroid lipofuscinosis gene MFSD8 are candidate risk factors for frontotemporal dementia

et al. 2018

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“…Retinal degeneration leading to visual impairment and ultimately blindness during the course of the disease has been reported as a typical neurologic symptom in patients with CLN7 with vLINCL phenotype, 7,8,[15][16][17][18][19]21,22,45 in a naturally occurring CLN7 canine model, 46 and in a hypomorphic mouse model of CLN7 disease. 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.…”

Section: Discussionmentioning

confidence: 99%

“…In fact, approximately 90% of patients with CLN7 develop visual failure during the course of the disease. 7,16,18,19,21,45,51 The morphologic and biochemical alterations in the retina of patients with CLN7 are, however, largely unknown and limited to morphologic data obtained from postmortem tissues of patients with vLINCL phenotype at the end stage of the disease. 15,22 Morphologic analyses of retinas from two patients with CLN7 aged 7 and 9 years and carrying the missense mutation p.Thr294Lys revealed a progressive retinal degeneration, with a complete loss of photoreceptor cells and a marked reduction of neuron numbers in the inner nuclear layer and the ganglion cell layer.…”

Section: Discussionmentioning

confidence: 99%

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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“…The consequences of MFSD8 mutation may be synaptic dysfunction resulting in disordered neurotransmitter release and local excitotoxicity. 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.…”

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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Clinico-pathological manifestations of variant late infantile neuronal ceroid lipofuscinosis (vLINCL) caused by a novel mutation in MFSD8 gene

Cited by 22 publications

References 15 publications

Rare variants in the neuronal ceroid lipofuscinosis gene MFSD8 are candidate risk factors for frontotemporal dementia

Rare variants in the neuronal ceroid lipofuscinosis gene MFSD8 are candidate risk factors for frontotemporal dementia

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

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