Peripheral GRN mRNA and Serum Progranulin Levels as a Potential Indicator for Both the Presence of Splice Site Mutations and Individuals at Risk for Frontotemporal Dementia

Article type: Research Article

Authors: Guven, Gamze^a | Bilgic, Başar^b | Tufekcioglu, Zeynep^b | Erginel Unaltuna, Nihan^a | Hanagasi, Hasmet^b | Gurvit, Hakan^b | Singleton, Andrew^c | Hardy, John^d | Emre, Murat^b | Gulec, Cagri^e | Bras, Jose^{d; f; g} | Guerreiro, Rita^{d; f; g; 1; 2; *} | Lohmann, Ebba^{h; i; 1; *}

Affiliations: [a] Department of Genetics, Aziz Sancar Institute for Experimental Medicine, Istanbul University, Istanbul, Turkey | [b] Department of Neurology, Behavioural Neurology and Movement Disorders Unit, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey | [c] Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA | [d] Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK | [e] Department of Medical Genetics, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey | [f] Department of Medical Sciences and Institute of Biomedicine – iBiMED, University of Aveiro, Aveiro, Portugal | [g] UK Dementia Research Institute at UCL (UK DRI), London, UK | [h] Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Germany | [i] DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany

Correspondence: [*] Correspondence to: Rita Guerreiro, PhD, UK Dementia Research Institute at UCL (UK DRI), London, UK. E-mail: [email protected] and Ebba Lohmann, MD, Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Germany. E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Note: [2] Current address: Van Andel Research Institute, 333 Bostwick Ave. N.E. Grand Rapids, Michigan 49503-2518. Current E-mail: [email protected].

Abstract: Progranulin (GRN) gene mutations are a major cause of frontotemporal dementia (FTD). Most mutations identified to date are null mutations, which are predicted to cause the pathology via haploinsufficiency. Decreased peripheral progranulin protein (PGRN) levels are associated with the presence of GRN null mutations and are accepted as reliable biomarkers. In this study, our aim was to test whether the presence of specific GRN splice site mutations (c.– 8+2T>G and c.708+6_9del), could be predicted by peripheral mRNA or protein GRN levels, by studying affected and asymptomatic individuals from FTD families. We also tested four missense GRN variants to assess if altered GRN levels depended on the type of mutation. Our results confirmed a reduction in both mRNA and protein PGRN levels in the splice site mutation carriers, which is consistent with previous reports for null mutations. Our results also suggested that both decreased peripheral GRN mRNA and serum PGRN levels indicate the presence of pathogenic mutations in affected individuals, and identify the asymptomatic individuals at risk, without previous knowledge of genetic status. Both inferences suggest a potential use of peripheral GRN mRNA or serum PGRN levels as biomarkers for families with FTD.

Keywords: ELISA, frontotemporal dementia, progranulin, serum, splice site mutation

DOI: 10.3233/JAD-180599

Journal: Journal of Alzheimer's Disease, vol. 67, no. 1, pp. 159-167, 2019