A Novel Splice-Acceptor Site Mutation in GRN (c.709-2 A>T) Causes Frontotemporal Dementia Spectrum in a Large Family from Southern Italy

Article type: Research Article

Authors: Sassi, Celeste^{a; b; c; d; 1} | Capozzo, Rosa^{e; 1} | Gibbs, Raphael^a | Crews, Cynthia^a | Zecca, Chiara^e | Arcuti, Simona^e | Copetti, Massimiliano^f | Barulli, Maria R.^e | Brescia, Vincenzo^g | Singleton, Andrew B.^a | Logroscino, Giancarlo^{e; h; *}

Affiliations: [a] Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA | [b] Reta Lila, Weston Research Laboratories, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK | [c] Department of Experimental Neurology, Center for Stroke Research Berlin (CSB), Charite’ Universitätmedizin, Berlin, Germany | [d] German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany | [e] Department of Clinical Research in Neurology, University of Bari at “Pia Fondazione Card G. Panico” Hospital, Tricase, Lecce, Italy | [f] Unit of Biostatistics, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy | [g] Unit of Laboratory Medicine, “Pia Fondazione Card. G. Panico”, Tricase, Lecce, Italy | [h] Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari ‘Aldo Moro’, Bari, Italy

Correspondence: [*] Correspondence to: Giancarlo Logroscino, MD, Department of Clinical Research in Neurology of the University of Bari at “Pia Fondazione Card G. Panico” Hospital – Via S Pio n 4, 73039Tricase, Lecce, Italy. Tel.: +39 0833773911/08; Fax: +39 0833773909; E-mail: [email protected].

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

Abstract: Heterozygous loss of function mutations in granulin represent a significant cause of frontotemporal lobar degeneration with ubiquitin and TDP-43 inclusions (FTLD-TDP). We report a novel GRN splice site mutation (c.709-2 A>T), segregating with frontotemporal dementia spectrum in a large family from southern Italy. The GRN c.709-2 A>T is predicted to result in the skipping of exon 8, leading to non-sense mediated mRNA decay. Moreover, the PGRN plasma levels in the GRN c.709-2 A>T carriers were significantly lower (24 ng/ml) compared to controls (142.7 ng/ml) or family members non-carriers (82.0 ng/ml) (p-value = 0.005, Kruskal Wallis), suggesting progranulin haploinsufficiency. We do not report any potential pathogenic GRN mutation in a follow-up cohort composed of 6 FTD families and 43 sporadic FTD cases, from the same geographic area. Our study suggests that GRN (c.709-2 A>T) is a novel and likely very rare cause of FTD in this Italian cohort. Finally, in line with previous studies, we show that GRN haploinsufficiency leads to a heterogeneous clinical picture, and plasma progranulin levels may be a reliable tool to identify GRN loss of function mutations. However, given that a) genetic and environmental factors, gender, and age may regulate PGRN plasma levels and b) plasma progranulin levels may not reflect PGRN levels in the central nervous system, we suggest that the measurement of progranulin in the plasma should always be coupled with genetic screening of GRN for mutations.

Keywords: Alzheimer’s disease, frontotemporal dementia, progranulin, splice site mutation

DOI: 10.3233/JAD-151170

Journal: Journal of Alzheimer's Disease, vol. 53, no. 2, pp. 475-485, 2016