Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21

Abstract

Two groups of neuroscientists have discovered that a mutation in the progranulin gene, which encodes a growth factor, can cause frontotemporal dementia (FTD). The condition, the second most common form of dementia among under-65s, impairs memory and personality and may also affect movement. The discovery may help to resolve confusion over the cause of the disease — mutations in a neighbouring gene called microtubule-associated protein tau were shown previously to be associated with some, but not all, cases of FTD. One of two papers detailing that mutations in the gene progranulin, which is found near MAPT on chromosome 17, can cause Frontotemporal dementia, a severe neurodegenerative disorder that can affect memory, personality and motor function. The progranulin gene encodes a secreted growth factor. Frontotemporal dementia (FTD) with ubiquitin-immunoreactive neuronal inclusions (both cytoplasmic and nuclear) of unknown nature has been linked to a chromosome 17q21 region (FTDU-17) containing MAPT (microtubule-associated protein tau)1,2,3. FTDU-17 patients have consistently been shown to lack a tau-immunoreactive pathology1,2,3, a feature characteristic of FTD with parkinsonism linked to mutations in MAPT (FTDP-17)4. Furthermore, in FTDU-17 patients, mutations in MAPT and genomic rearrangements in the MAPT region have been excluded by both genomic sequencing5 and fluorescence in situ hybridization on mechanically stretched chromosomes6. Here we demonstrate that FTDU-17 is caused by mutations in the gene coding for progranulin (PGRN), a growth factor involved in multiple physiological and pathological processes including tumorigenesis7. Besides the production of truncated PGRN proteins due to premature stop codons8, we identified a mutation within the splice donor site of intron 0 (IVS0 + 5G > C), indicating loss of the mutant transcript by nuclear degradation. The finding was made within an extensively documented Belgian FTDU-17 founder family3. Transcript and protein analyses confirmed the absence of the mutant allele and a reduction in the expression of PGRN. We also identified a mutation (c.3G > A) in the Met1 translation initiation codon, indicating loss of PGRN due to lack of translation of the mutant allele. Our data provide evidence that PGRN haploinsufficiency leads to neurodegeneration because of reduced PGRN-mediated neuronal survival. Furthermore, in a Belgian series of familial FTD patients, PGRN mutations were 3.5 times more frequent than mutations in MAPT, underscoring a principal involvement of PGRN in FTD pathogenesis.