Progranulin Mutations as Risk Factors for Alzheimer Disease

JAMA neurology 04/2013; 70(6):1-5. DOI: 10.1001/2013.jamaneurol.393
Source: PubMed


Mutations in the progranulin gene are known to cause diverse clinical syndromes, all attributed to frontotemporal lobar degeneration. We describe 2 patients with progranulin gene mutations and evidence of Alzheimer disease (AD) pathology. We also conducted a literature review.

This study focused on case reports of 2 unrelated patients with progranulin mutations at the University of California, San Francisco, Memory and Aging Center. One patient presented at age 65 years with a clinical syndrome suggestive of AD and showed evidence of amyloid aggregation on positron emission tomography. Another patient presented at age 54 years with logopenic progressive aphasia and, at autopsy, showed both frontotemporal lobar degeneration with TDP-43 inclusions and AD.

Conclusions and relevance:
In addition to autosomal-dominant frontotemporal lobar degeneration, mutations in the progranulin gene may be a risk factor for AD clinical phenotypes and neuropathology.

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Available from: Jennifer S Yokoyama, Aug 27, 2014
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    • "In this first systematic mutation screen of 124 subjects with clinical PCA or posterior AD pathology, we used a customized Illumina exome genotyping array, NeuroX, to evaluate genes known to harbor pathogenic variants in early-onset AD [APP (Goate et al., 1991), PSEN1 (Sherrington et al., 1995), and PSEN2 (Rogaev et al., 1995)], LOAD [APOE (Yu et al., 2014) and TREM2 (Guerreiro and Hardy, 2013; Kleinberger et al., 2014)], FTD [GRN (Perry et al., 2013; Wojtas et al., 2012) and MAPT (Carney et al., 2014; Wojtas et al., 2012), and CJD [PRNP (Guerreiro et al., 2014)], for their role in PCA. NeuroX is enriched for risk variants involved in neurological disorders, thus providing an efficient platform for rapid screening of genes of interest (Ghani et al., 2015). "
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    ABSTRACT: Posterior cortical atrophy (PCA) is an understudied visual impairment syndrome most often due to "posterior Alzheimer's disease (AD)" pathology. Case studies detected mutations in PSEN1, PSEN2, GRN, MAPT, and PRNP in subjects with clinical PCA. To detect the frequency and spectrum of mutations in known dementia genes in PCA, we screened 124 European-American subjects with clinical PCA (n = 67) or posterior AD neuropathology (n = 57) for variants in genes implicated in AD, frontotemporal dementia, and prion disease using NeuroX, a customized exome array. Frequencies in PCA of the variants annotated as pathogenic or potentially pathogenic were compared against ∼4300 European-American population controls from the NHLBI Exome Sequencing Project. We identified 2 rare variants not previously reported in PCA, TREM2 Arg47His, and PSEN2 Ser130Leu. No other pathogenic or potentially pathogenic variants were detected in the screened dementia genes. In this first systematic variant screen of a PCA cohort, we report 2 rare mutations in TREM2 and PSEN2, validate our previously reported APOE ε4 association, and demonstrate the utility of NeuroX.
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    • "Loss of function mutations in the GRN gene are related to pro-inflammatory cytokine dysregulation in FTLD patients [18]. In addition, mutations in GRN are also associated with increased prevalence of specific and related autoimmune diseases, including inflammatory arthritis [19] [20]. PGRN binding receptors and signaling in mediating its antiinflammatory functions in neurons still remain elusive. "
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    ABSTRACT: We previously reported that PGRN directly bound to TNF receptors (TNFR) in vitro and in chondrocytes (Tang, et al, Science, 2011). Here we report that PGRN also associated with TNFR in splenocytes, and inhibited the binding of TNFα to immune cells. Proper folding of PGRN is essential for its binding to TNFR, as DTT treatment abolished its binding to TNFR. In contrast, the binding of PGRN to Sortilin was enhanced by DTT. Protein interaction assays with mutants of the TNFR extracellular domain demonstrated that CRD2 and CRD3 of TNFR are important for the interaction with PGRN, similar to the binding to TNFα. Taken together, these findings provide the molecular basis underlying PGRN/TNFR interaction and PGRN-mediated anti-inflammatory activity in various autoimmune diseases and conditions.
    Full-text · Article · Sep 2013 · FEBS letters

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