Association of TMEM106B Gene Polymorphism With Age at Onset in Granulin Mutation Carriers and Plasma Granulin Protein Levels

Department of Psychiatry, Washington University School of Medicine, 660 S Euclid Avenue, St Louis, MO 63110, USA.
Archives of neurology (Impact Factor: 7.01). 05/2011; 68(5):581-6. DOI: 10.1001/archneurol.2010.350
Source: PubMed

ABSTRACT To test whether rs1990622 (TMEM106B) is associated with age at onset (AAO) in granulin (GRN) mutation carriers and with plasma GRN levels in mutation carriers and healthy, elderly individuals. Rs1990622 (TMEM106B) was identified as a risk factor for frontotemporal lobar degeneration with TAR DNA-binding protein inclusions (FTLD-TDP) in a recent genome-wide association.
Rs1990622 was genotyped in GRN mutation carriers and tested for association with AAO using the Kaplan-Meier method and a Cox proportional hazards model.
Alzheimer's Disease Research Center. Subjects We analyzed 50 affected and unaffected GRN mutation carriers from 4 previously reported FTLD-TDP families (HDDD1, FD1, HDDD2, and the Karolinska family). The GRN plasma levels were also measured in 73 healthy, elderly individuals.
Age at onset and GRN plasma levels.
The risk allele of rs1990622 was associated with a mean decrease of the AAO of 13 years (P = 9.9 × 10(-7)) and with lower plasma GRN levels in both healthy older adults (P = 4 × 10(-4)) and GRN mutation carriers (P = .0027). Analysis of the HapMap database identified a nonsynonymous single-nucleotide polymorphism rs3173615 (T185S) in perfect linkage disequilibrium with rs1990622.
The association of rs1990622 with AAO explains, in part, the wide range in the AAO of disease among GRN mutation carriers. We hypothesize that rs1990622 or another variant in linkage disequilibrium could act in a manner similar to APOE in Alzheimer disease, increasing risk for disease in the general population and modifying AAO in mutation carriers. Our results also suggest that genetic variation in TMEM106B may influence risk for FTLD-TDP by modulating secreted levels of GRN.

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Available from: Sarah Bertelsen, Aug 26, 2015
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    • "The human linkage of FTLD-TDP risk to TMEM106B allele suggests that T185S variation plays a role. While this genetic variation alters PGRN levels in serum (Cruchaga et al., 2011; Finch et al., 2011), the effect may be direct or indirect. Tissue culture studies reveal either small or no effect of TMEM106B variants on PGRN levels (Brady et al., 2013; Lang et al., 2012). "
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    ABSTRACT: Fronto-temporal lobar degeneration with TDP-43 (FTLD-TDP) is a fatal neurodegeneration. TMEM106B variants are linked to FTLD-TDP risk, and TMEM106B is lysosomal. Here, we focus on neuronal TMEM106B, and demonstrate co-localization and traffic with lysosomal LAMP-1. pH-sensitive reporters demonstrate that the TMEM106B C-terminus is lumenal. The TMEM106B N-terminus interacts with endosomal adaptors and other TMEM106 proteins. TMEM106B knockdown reduces neuronal lysosomal number and diameter by STED microscopy, and overexpression enlarges LAMP-positive structures. Reduction of TMEM106B increases axonally transported lysosomes, while TMEM106B elevation inhibits transport and yields large lysosomes in the soma. TMEM106B overexpression alters lysosomal stress signaling, causing a translocation of the mTOR-sensitive transcription factor, TFEB, to neuronal nuclei. TMEM106B loss-of-function delays TFEB translocation after Torin-1-induced stress. Enlarged TMEM106B-overexpressing lysosomes maintain organelle integrity longer after lysosomal photodamage than do control lysosomes, while small TMEM106B-knockdown lysosomes are more sensitive to illumination. Thus, neuronal TMEM106B plays a central role in regulating lysosomal size, motility and responsiveness to stress, highlighting the possible role of lysosomal biology in FTLD-TDP.
    Molecular and Cellular Neuroscience 07/2014; 61. DOI:10.1016/j.mcn.2014.07.006 · 3.73 Impact Factor
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    • "Because FTLD is associated with loss-of-function mutations in GRN, one might predict that the protein this gene encodes (PGRN) would be diminished by the risk-associated allele of TMEM106B. Indeed, higher levels of PGRN are detected in the plasma of individuals carrying the protective S185 allele (or SNPs in linkage disequilibrium with that allele) (Cruchaga et al. 2011; Finch et al. 2011). However, Nicholson et al. (2013) report that overexpression of either the T or the S variant of TMEM106B leads to elevated steady-state levels of PGRN protein. "
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    ABSTRACT: Read the full article ‘TMEM106B p.T185S regulates TMEM106B protein levels: implications for frontotemporal dementia’ on doi:10.1111/jnc.12329.
    Journal of Neurochemistry 07/2013; DOI:10.1111/jnc.12357 · 4.24 Impact Factor
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    • "Additionally, a significant association was observed between rs1990622 and progranulin levels in plasma of unaffected controls, with higher levels of progranulin in C-allele carriers (Finch et al., 2011). In an independent study, Cruchaga et al. showed an association of rs1990622 with age at onset in GRN mutation carriers, with the C-allele delaying the age at onset by 13 years (Cruchaga et al., 2011). These authors also showed higher plasma progranulin levels in GRN mutation carriers and healthy adults carrying the rs1990622 C-allele. "
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    ABSTRACT: Frontotemporal lobar degeneration (FTLD) is a common neurodegenerative disorder that predominantly affects individuals under the age of 65. It is known that the most common pathological subtype is FTLD with TAR DNA-binding protein 43 inclusions (FTLD-TDP). FTLD has a strong genetic component with about 50% of cases having a positive family history. Mutations identified in the progranulin gene (GRN) have been shown to cause FTLD-TDP as a result of progranulin haploinsufficiency. These findings suggest a progranulin-dependent mechanism in this pathological FTLD subtype. Thus, identifying regulators of progranulin levels is essential for new therapies and treatments for FTLD and related disorders. In this review, we discuss the role of genetic studies in identifying progranulin regulators, beginning with the discovery of pathogenic GRN mutations and additional GRN risk variants. We also cover more recent genetic advances, including the detection of variants in the transmembrane protein 106 B gene that increase FTLD-TDP risk presumably by modulating progranulin levels and the identification of a potential progranulin receptor, sortilin. This review highlights the importance of genetic studies in the context of FTLD and further emphasizes the need for future genetic and cell biology research to continue the effort in finding a cure for progranulin-related diseases.
    Journal of Molecular Neuroscience 05/2011; 45(3):532-7. DOI:10.1007/s12031-011-9554-y · 2.76 Impact Factor
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