Estimating the age of the most common Italian GRN mutation: walking back to Canossa times.
Mutations in the progranulin gene (GRN) were first implicated in frontotemporal lobar degeneration in 2006. The GRN p.Leu271LeufsX10 mutation is one of the most common GRN mutations worldwide. To gain further insight into the origin of this mutation in Italy, we performed a haplotype sharing analysis (32 families, residents of Lombardy) and refined the GRN p.Leu271LeufsX10 mutation dating. We showed that almost all families (30/32) can be traced to a single founder. We further estimated the age of this mutation using different methods and population growth rates both for Italy and Lombardy. Using DMLE, we dated the origin of this mutation to the Middle Ages, at the turn of the first millennium (phased families only, Italy: 39 and Lombardy: 32 generations ago; all families Italy: 45 and Lombardy 38 generations ago). Mutation dating was slightly postdated using Estiage (phased families only: 15 generations ago; all families: 20 generation ago). From a translational perspective, targeting mutation carriers offers a unique model to test disease-modifying drugs in clinical trials.
NeuroBioGen Lab-Memory Clinic, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy. lbenussi@fatebenefratelli.it
Luisa
L
Benussi
Rosa
R
Rademakers
Nicola J
NJ
Rutherford
Aleksandra
A
Wojtas
Michela
M
Glionna
Anna
A
Paterlini
Valentina
V
Albertini
Thomas
T
Bettecken
Giuliano
G
Binetti
Roberta
R
Ghidoni
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000453:epidemiology* / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D007558:Italy / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D000077153:Progranulins; D013997:Time Factors
C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins