The Rise of the GRN C157KfsX97 Mutation in Southern Italy: Going Back to the Fall of the Western Roman Empire

Article type: Research Article

Authors: Coppola, Cinzia^{a; *} | Saracino, Dario^b | Oliva, Mariano^a | Puoti, Gianfranco^a | Lus, Giacomo^a | Le Ber, Isabelle^b | Pariente, Jérémie^c | Tessitore, Alessandro^a | Benussi, Luisa^d | Ghidoni, Roberta^d | Carrara, Matteo^e | Ricci, Martina^f | Redaelli, Veronica^f | Tiraboschi, Pietro^f | Caroppo, Paola^f | Giaccone, Giorgio^f | Bonavita, Simona^a | Rossi, Giacomina^f

Affiliations: [a] Department of Advanced Medical and Surgical Sciences, University of Campania “L. Vanvitelli”, Naples, Italy | [b] Sorbonne Université, Inserm U1127, CNRS UMR 7225, Institut du Cerveau (ICM), AP-HP - Hôpital Pitié-Salpêtrière, Paris, France and Centre de référence des démences rares ou précoces, IM2A, Département de Neurologie, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France | [c] Department of Neurology, Toulouse University Hospital, Toulouse, France | [d] Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy | [e] Service of Statistics, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy | [f] Division of Neurology V - Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

Correspondence: [*] Correspondence to: Cinzia Coppola, Second Division of Neurology, University of Campania “Luigi Vanvitelli”, Isola 8 – Edificio 10 Policlinico “Federico II” via Pansini 5, 80131 Naples, Italy. Tel.: +39 0815666811; Fax: +39 0815666805; E-mail: [email protected].

Abstract: Background:Frontotemporal lobar degeneration (FTLD) designates a group of neurodegenerative diseases with remarkable clinical, pathological, and genetic heterogeneity. Mutations in progranulin gene (GRN) are among the most common causes of familial FTLD. The GRN C157KfsX97 mutation is the most frequent mutation occurring in Southern Italy and has been already described in a previous work. Objective:In this study, we reported on additional cases carrying the same mutation and performed a genetic study on the whole cohort, aiming at demonstrating the existence of a founder effect and estimating the age of this mutation. Methods/Results:Based on the haplotype sharing analysis, a founder effect was highly probable, while the age of the mutation, estimated by means of DMLE+ software, resulted in a range between 52 and 82 generations, with the highest frequency at about 62 generations, 1,550 years ago. Conclusion:This is the first study that reports the age estimation of the most recent common ancestor for the GRN C157KfsX97 mutation recurring in Southern Italy. Mutation dating in a geographically restricted population may be useful in order to plan genetic counseling and screening programs in the field of public health.

Keywords: Common founder, frontotemporal lobar degeneration, GRN , haplotype, mutation, mutation dating

DOI: 10.3233/JAD-200924

Journal: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 387-394, 2020