NeuroBioGen Lab-Memory Clinic, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
J Alzheimers Dis. 2013;33(1):69-76. doi: 10.3233/JAD-2012-121306.
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.
GRN 基因中的突变（GRN）于 2006 年首次被认为与额颞叶变性有关。GRN p.Leu271LeufsX10 突变是全球最常见的 GRN 突变之一。为了更深入地了解该突变在意大利的起源，我们进行了单倍型共享分析（32 个家庭，伦巴第大区居民）并完善了 GRN p.Leu271LeufsX10 突变的追溯日期。结果表明，几乎所有的家庭（30/32）都可以追溯到一个单一的祖先。我们进一步使用不同的方法和意大利及伦巴第大区的人口增长率来估计该突变的年龄。使用 DMLE，我们将该突变的起源追溯到中世纪，即公元 1000 年左右（仅阶段性家庭，意大利：39 代和伦巴第：32 代以前；所有家庭意大利：45 代和伦巴第 38 代以前）。使用 Estiage 略微推迟了突变的追溯日期（仅阶段性家庭：15 代以前；所有家庭：20 代以前）。从转化的角度来看，针对突变携带者提供了一个独特的模型，可以在临床试验中测试疾病修饰药物。
