Serum Progranulin Levels in Patients with Frontotemporal Lobar Degeneration and Alzheimer's Disease: Detection of GRN Mutations in a Spanish Cohort

Article type: Research Article

Authors: Antonell, Anna^a | Gil, Silvia^a | Sánchez-Valle, Raquel^a | Balasa, Mircea^a | Bosch, Beatriz^a | Prat, Ma Carmen^b | Chiollaz, Anne-Cécile^a | Fernández, Manel^a | Yagüe, Jordi^c | Molinuevo, José Luis^a | Lladó, Albert^{a; *}

Affiliations: [a] Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain | [b] Cognitive Disorders Unit, Consorci Sanitari Parc Taulí, Sabadell, Spain | [c] Department of Immunology, Hospital Clínic, Institut de Recerca Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain

Correspondence: [*] Correspondence to: Albert Lladó, MD, PhD, Alzheimer's Disease and Other Cognitive Disorders Unit, Hospital Clínic, C/Villarroel, 170, 08036 Barcelona, Spain. Tel.: +34 932275785; Fax: +34 932275783; E-mail: [email protected].

Abstract: Progranulin gene (GRN) mutations cause frontotemporal lobar degeneration (FTLD) with TDP43-positive inclusions, although its clinical phenotype is heterogeneous and includes patients classified as behavioral variant-FTLD (bvFTLD), progressive non-fluent aphasia (PNFA), corticobasal syndrome, Alzheimer's disease (AD), or Parkinson's disease (PD). Our main objective was to study if low serum progranulin protein (PGRN) levels may detect GRN mutations in a Spanish cohort of patients with FTLD or AD. Serum PGRN levels were measured in 112 subjects: 17 bvFTLD, 20 PNFA, 4 semantic dementia, 34 sporadic AD, 9 AD-PSEN1 mutation carriers, 10 presymptomatic-PSEN1 mutation carriers, and 18 control individuals. We detected 5 patients with PGRN levels below 94 ng/mL: two of them had a clinical diagnosis of bvFTLD, two of PNFA, and one of AD. The screening for GRN mutations detected two probable pathogenic mutations (p.C366fsX1 and a new mutation: p.V279GfsX5) in three patients and one mutation of unclear pathogenic nature (p.C139R) in one patient. The other patient showed a normal GRN sequence but carried a PRNP gene mutation. We observed no differences in serum PGRN levels between controls (mean = 145.5 ng/mL, SD = 28.5) and the other neurodegenerative diseases, except for the carriers of pathological GRN gene mutations (mean = 50.5 ng/mL, SD = 21.2). Null GRN mutation carriers also showed lower serum PGRN levels than the patient who was a carrier of p.C139R (92.3 ng/mL) and the one who was a carrier of the PRNP mutation (76.9 ng/mL). In conclusion, we detected GRN null mutations in patients with severely reduced serum PGRN levels, but not in patients with slightly reduced PGRN levels.

Keywords: Alzheimer's disease, biomarker, exon skipping, frameshift, frontotemporal lobar degeneration, mutation, progranulin, serum, splicing

DOI: 10.3233/JAD-2012-112120

Journal: Journal of Alzheimer's Disease, vol. 31, no. 3, pp. 581-591, 2012