TY - JOUR
T1 - Estimating the age of the most common italian grn mutation
T2 - Walking back to Canossa Times
AU - Benussi, Luisa
AU - Rademakers, Rosa
AU - Rutherford, Nicola J.
AU - Wojtas, Aleksandra
AU - Glionna, Michela
AU - Paterlini, Anna
AU - Albertini, Valentina
AU - Bettecken, Thomas
AU - Binetti, Giuliano
AU - Ghidoni, Roberta
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
KW - Clinical phenotype
KW - FTLD
KW - GRN
KW - disease haplotypes
KW - founder
KW - mutation
KW - pedigrees
KW - progranulin
UR - http://www.scopus.com/inward/record.url?scp=84872461917&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84872461917&partnerID=8YFLogxK
U2 - 10.3233/JAD-2012-121306
DO - 10.3233/JAD-2012-121306
M3 - Article
C2 - 22890101
AN - SCOPUS:84872461917
SN - 1387-2877
VL - 33
SP - 69
EP - 76
JO - Journal of Alzheimer's Disease
JF - Journal of Alzheimer's Disease
IS - 1
ER -