Rare variants in the neuronal ceroid lipofuscinosis gene MFSD8 are candidate risk factors for frontotemporal dementia
- 622 Downloads
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 that 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 = 3541), and found suggestive evidence that gene-wide aggregate rare variant burden in MFSD8 is associated 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 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 an increase 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.
KeywordsAutophagy Frontotemporal dementia Genetics Lysosomes Neurodegeneration Neuronal ceroid lipofuscinosis
We thank Jason Chen and the New York Genome Center for technical support of whole genome sequencing. Primary support for this study was provided by the Rainwater Charitable Foundation (JSY, AMC, SEL, GC, WWS, YH). Additional support was provided by the Bluefield Project to Cure FTD (JSY, WWS), Association for Frontotemporal Degeneration Susan Marcus Memorial Fund Clinical Research Grant (JSY), Larry L. Hillblom Foundation 2016-A-005-SUP (JSY), National Institute on Aging K01 AG049152 (JSY), John Douglas French Alzheimer’s Foundation (JSY, GC), National Institute on Aging P01 AG1972403 (BLM), National Institute on Aging P50 AG023501 (BLM), National Institute on Aging R01 AG023501, AG048030, NS079725 (YH), and R01 AG054108 (AMC), National Institutes of Health F32 AG050404 (DWS), RC1 AG035610 (GC), and R01 AG26938 (GC). Takeda Pharmaceutical Company Limited (GC). We acknowledge the support of the National Institute of Neurological Disorders and Stroke Informatics Center for Neurogenetics and Neurogenomics, P30 NS062691 (GC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Experimental design: EGG, NS, SEL, AMC, JSY. Data collection: EGG, NS, MB, JNC, DWS, JHH, EMR, AD, VVB, DD, SS. Data analysis and interpretation: EGG, NS, MB, JNC, DWS, JHH, LWB, EMR, SPR, SS, LTG, WWS, BLM, GC, SEL, AMC, JSY. Subject recruitment: AK, LTG, WWS, BLM. Provided technical and/or administrative support: ANL, AK, MEB, YH, RMM. Writing the manuscript: EGG, NS, MB, AMC, JSY.
Compliance with ethical standards
Conflict of interest
YH is a co-founder and SAB member of E-Scape Bio, Inc. AMC is a co-founder and SAB member of Selphagy Inc.
- 3.Almeida MR, Macário MC, Ramos L, Baldeiras I, Ribeiro MH, Santana I (2016) Portuguese family with the co-occurrence of frontotemporal lobar degeneration and neuronal ceroid lipofuscinosis phenotypes due to progranulin gene mutation. Neurobiol Aging 41:200.e1–200.e5. https://doi.org/10.1016/j.neurobiolaging.2016.02.019 CrossRefGoogle Scholar
- 20.Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC et al (2013) National Institute on Aging—Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement 8:1–13. https://doi.org/10.1016/j.jalz.2011.10.007.National CrossRefGoogle Scholar
- 33.Lee S, Emond MJ, Bamshad MJ, Barnes KC, Rieder MJ, Nickerson DA et al (2012) Optimal unified approach for rare-variant association testing with application to small-sample case–control whole-exome sequencing studies. Am J Hum Genet 91:224–237. https://doi.org/10.1016/j.ajhg.2012.06.007 CrossRefGoogle Scholar
- 39.Mandel H, Cohen Katsanelson K, Khayat M, Chervinsky I, Vladovski E, Iancu TC et al (2014) Clinico-pathological manifestations of variant late infantile neuronal ceroid lipofuscinosis (vLINCL) caused by a novel mutation in MFSD8 gene. Eur J Med Genet 57:607–612. https://doi.org/10.1016/j.ejmg.2014.09.004 CrossRefGoogle Scholar
- 45.Mercy L, Hodges JR, Dawson K, Barker RA, Brayne C (2008) Incidence of early-onset dementias in Cambridgeshire, United Kingdom. Neurology 71:1496–1499. https://doi.org/10.1212/01.wnl.0000334277.16896.fa CrossRefGoogle Scholar
- 54.Pottier C, Bieniek KF, Finch N, van de Vorst M, Baker M, Perkersen R et al (2015) Whole-genome sequencing reveals important role for TBK1 and OPTN mutations in frontotemporal lobar degeneration without motor neuron disease. Acta Neuropathol 130:77–92. https://doi.org/10.1007/s00401-015-1436-x CrossRefGoogle Scholar
- 57.Rascovsky K, Hodges JR, Kipps CM, Johnson JK, Seeley WW, Mendez MF et al (2007) Diagnostic criteria for the behavioral variant of frontotemporal dementia (bvFTD): current limitations and future directions. Alzheimer Dis Assoc Disord 21:S14–S18. https://doi.org/10.1097/WAD.0b013e31815c3445 CrossRefGoogle Scholar
- 59.Roosing S, van den Born LI, Sangermano R, Banfi S, Koenekoop RK, Zonneveld-Vrieling MN et al (2015) Mutations in MFSD8, encoding a lysosomal membrane protein, are associated with nonsyndromic autosomal recessive macular dystrophy. Ophthalmology 122:170–179. https://doi.org/10.1016/j.ophtha.2014.07.040 CrossRefGoogle Scholar
- 62.Sharifi A, Kousi M, Sagné C, Bellenchi GC, Morel L, Darmon M et al (2010) Expression and lysosomal targeting of CLN7, a major facilitator superfamily transporter associated with variant late-infantile neuronal ceroid lipofuscinosis. Hum Mol Genet 19:4497–4514. https://doi.org/10.1093/hmg/ddq381 CrossRefGoogle Scholar
- 77.Yokoyama JS, Lee SE (2016) Molecular pathways leading to the clinical phenomenology of frontotemporal dementia. In: Genomics, circuits, and pathways in clinical neuropsychiatry. https://doi.org/10.1016/B978-0-12-800105-9.00033-0
- 78.Yu CE, Bird TD, Bekris LM, Montine TJ, Leverenz JB, Steinbart E et al (2010) The spectrum of mutations in progranulin: a collaborative study screening 545 cases of neurodegeneration. Arch Neurol 67:161–170Google Scholar