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.
(c) 2007 Wiley-Liss, Inc.