Uncommon PGRN deletion and FTD responsible for phenotype variability in three familial cases.

Mutations in Progranulin (PGRN) gene have been genetically associated with fronto-temporal dementia (FTD), although the neurobiology of this secreted glycoprotein is still unclear. We identified three familial cases having a rare +5 deletion in exon six of PGRN gene (g.101349_101355delCTGCTGT) as causative of frameshift mutation. This mutation is not considered frequent and already described in two apparently sporadic case of FTD only, but never associated with familial cases. Our patients showed also heterogeneous clinical phenotypes, such as behavioral variant (bv-FTD) in men and primary progressive aphasia (PPA) in women. Quantitative RT-PCR of PGRN gene expression in WBC shows an unusual increasing of expression, while protein analyses of plasma concentration detected a PGRN protein deficiency. Using allele-specific PCR mutation-primers (ARMS), this mutation was searched in three hundreds healthy controls matched by age, sex and geographic regions and no deletion was ever found. The findings provide convincing evidence of the putative role of PGRN in the genetic etiology of FTD and show a link between FTD and ex 6-del PGRN mutations, which probably are more frequent than previously considered. The described mutation express two different gender linked phenotypes bv-FTD in men and PPA in women. Although we believe that this is the product of a founder effect, we yet cannot prove at this stage. Our findings imply that PGRN is essential for neuronal survival and even partial loss of PGRN eventually leads to neurodegeneration.