Refining frontotemporal dementia with parkinsonism linked to chromosome 17: introducing FTDP-17 (MAPT) and FTDP-17 (PGRN)

Abstract

Frontotemporal dementia with parkinsonism (FTDP) is a major neurodegenerative syndrome, particularly for those with symptoms beginning before age 65 years. A spectrum of degenerative disorders can present as sporadic or familial FTDP. Mutations in the gene encoding the microtubule-associated protein tau (MAPT; OMIM +157140) on chromosome 17 have been found in many kindreds with familial FTDP. Several other kindreds with FTDP had been linked to chromosome 17, but they had ubiquitin-positive inclusions rather than tauopathy pathology and no mutations in MAPT. This conundrum was solved in 2006 with the identification of mutations in the gene encoding progranulin (PGRN; OMIM *138945), which is only 1.7 Mb centromeric to MAPT on chromosome 17. In this review, we compare and contrast the demographic, clinical, radiologic, neuropathologic, genetic, and pathophysiologic features in patients with FTDP linked to mutations in MAPT and PGRN, highlighting the many similarities but also a few important differences. Our findings describe an intriguing oddity of nature in which 2 genes can cause a similar phenotype through apparently different mechanisms yet reside so near to each other on the same chromosome.

Figure

Sequence chromatograms of exon 11 of the progranulin gene (PGRN) from a control individual (upper panel) and a patient with frontotemporal dementia carrying the common c.1477C>T mutation (lower panel). Below each chromatogram, the predicted amino acid sequence of the PGRN protein including codon numbering is shown. The arrow denotes the position of the mutation in the chromatogram. The PGRN c.1477C>T mutation results in a premature termination of the coding sequence at codon 493, inducing the degradation of mutant PGRN RNA by nonsense-mediated decay and loss of PGRN protein (haploinsufficiency).