Gijselinck I, van der Zee J, Engelborghs S, Goossens D, Peeters K, Mattheijssens M, Corsmit E, Del-Favero J, De Deyn P P, Van Broeckhoven C, Cruts M
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Institute for Biotechnology (VIB), University of Antwerp, Antwerpen, Belgium.
Hum Mutat. 2008 Jan;29(1):53-8. doi: 10.1002/humu.20651.
Ubiquitin-positive, tau-negative, frontotemporal dementia (FTD) is caused by null mutations in progranulin (PGRN; HUGO gene symbol GRN), suggesting a haploinsufficiency mechanism. Since whole gene deletions also lead to the loss of a functional allele, we performed systematic quantitative analyses of PGRN in a series of 103 Belgian FTD patients. We identified in one patient (1%) a genomic deletion that was absent in 267 control individuals. The deleted segment was between 54 and 69 kb in length and comprised PGRN and two centromeric neighboring genes RPIP8 (HUGO gene symbol RUNDC3A) and SLC25A39. The patient presented clinically with typical FTD without additional symptoms, consistent with haploinsufficiency of PGRN being the only gene contributing to the disease phenotype. This study demonstrates that reduced PGRN in absence of mutant protein is sufficient to cause neurodegeneration and that previously reported PGRN mutation frequencies are underestimated.
泛素阳性、tau蛋白阴性的额颞叶痴呆（FTD）由原颗粒蛋白（PGRN；人类基因组组织基因符号GRN）的无效突变引起，提示单倍剂量不足机制。由于全基因缺失也会导致功能性等位基因的丢失，我们对103例比利时FTD患者进行了PGRN的系统定量分析。我们在1例患者（1%）中鉴定出一种基因组缺失，267名对照个体中未发现该缺失。缺失片段长度在54至69 kb之间，包含PGRN以及两个着丝粒相邻基因RPIP8（人类基因组组织基因符号RUNDC3A）和SLC25A39。该患者临床上表现为典型的FTD，无其他症状，这与PGRN单倍剂量不足是导致疾病表型的唯一基因相符。这项研究表明，在没有突变蛋白的情况下PGRN减少足以导致神经退行性变，并且先前报道的PGRN突变频率被低估了。
