Estimating the Age of the Most Common Italian GRN Mutation: Walking Back to Canossa Times

被引：17

作者：

Benussi, Luisa ^{[1
]}

Rademakers, Rosa ^{[2
]}

Rutherford, Nicola J. ^{[2
]}

Wojtas, Aleksandra ^{[2
]}

Glionna, Michela ^{[1
]}

Paterlini, Anna ^{[3
]}

Albertini, Valentina ^{[3
]}

Bettecken, Thomas ^{[4
]}

Binetti, Giuliano ^{[1
]}

Ghidoni, Roberta ^{[3
]}

机构：

[1] IRCCS Ist Ctr San Giovanni di Dio Fatebenefratell, Memory Clin, NeuroBioGen Lab, I-25125 Brescia, Italy

[2] Mayo Clin, Coll Med, Dept Neurosci, Jacksonville, FL 32224 USA

[3] IRCCS Ist Ctr San Giovanni di Dio Fatebenefratell, Prote Unit, I-25125 Brescia, Italy

[4] Max Planck Inst Psychiat, CAGT Ctr Appl Genotying Munich, D-80804 Munich, Germany

来源：

JOURNAL OF ALZHEIMERS DISEASE | 2013年 / 33卷 / 01期

关键词：

Clinical phenotype; disease haplotypes; founder; FTLD; GRN; mutation; pedigrees; progranulin; FRONTOTEMPORAL LOBAR DEGENERATION; PROGRANULIN MUTATIONS; CLINICAL-DIAGNOSIS; DEMENTIA; HETEROGENEITY; GENE; FTLD; DELETION; VARIABILITY; DISEASE;

D O I：

10.3233/JAD-2012-121306

中图分类号：

Q189 [神经科学];

学科分类号：

071006 [神经生物学];

摘要：

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.

引用

页码：69 / 76

页数：8

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