van der Zee Julie, Le Ber Isabelle, Maurer-Stroh Sebastian, Engelborghs Sebastiaan, Gijselinck Ilse, Camuzat Agnès, Brouwers Nathalie, Vandenberghe Rik, Sleegers Kristel, Hannequin Didier, Dermaut Bart, Schymkowitz Joost, Campion Dominique, Santens Patrick, Martin Jean-Jacques, Lacomblez Lucette, De Pooter Tim, Peeters Karin, Mattheijssens Maria, Vercelletto Martine, Van den Broeck Marleen, Cruts Marc, De Deyn Peter P, Rousseau Frederic, Brice Alexis, Van Broeckhoven Christine
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium.
Hum Mutat. 2007 Apr;28(4):416. doi: 10.1002/humu.9484.
Null mutations in the progranulin gene (GRN, PGRN) were recently identified as the causal mechanism underlying frontotemporal dementia (FTD) with ubiquitin-positive brain pathology linked to chromosome 17 (FTDU-17). In a Belgian and French FTD series comprising 332 patients, we reported 13 PGRN null mutations which were mainly nonsense and frameshift mutations resulting in premature stop codons. Here we report in the same patient series three missense mutations of which two (c.743C>T, p.Pro248Leu and c.1294C>T, p.Arg432Cys) were predicted in silico to severely affect protein folding and/or processing leading to PGRN protein haploinsufficiency. In addition, we observed three sequence variations in the 5' regulatory region that might potentially affect PGRN transcription activity. Our findings extend the mutation spectrum in PGRN leading to loss of functional PGRN as the basis for FTD.
颗粒前体蛋白基因（GRN，PGRN）的无效突变最近被确定为与17号染色体相关的泛素阳性脑病变的额颞叶痴呆（FTD）（FTDU - 17）的致病机制。在一个由332名患者组成的比利时和法国FTD系列中，我们报告了13个PGRN无效突变，这些突变主要是无义突变和移码突变，导致过早出现终止密码子。在此，我们在同一患者系列中报告了三个错义突变，其中两个（c.743C>T，p.Pro248Leu和c.1294C>T，p.Arg432Cys）经计算机模拟预测会严重影响蛋白质折叠和/或加工，导致PGRN蛋白单倍剂量不足。此外，我们在5'调控区观察到三个序列变异，它们可能会潜在影响PGRN的转录活性。我们的研究结果扩展了PGRN导致功能性PGRN缺失的突变谱，这是FTD的基础。
