Finding the progranulin mutations solves a long-standing mystery—what causes familial FTD cases that are clearly linked to chromosome 17q21, but carry no detectable mutations in MAPT, the tau gene. As it turns out, the answer was close at hand. In what Hutton and colleagues call an “extraordinary coincidence,” the PGRN sits just 1.7 Mb away from MAPT, and despite the proteins having no apparent functional link, mutations in both genes each cause a clinically equivalent neurological disease.

The characteristic personality and behavior changes of FTD result from neuronal loss in the frontal and temporal regions of the brain. Nearly 10 years ago, mutations in the microtubule-associated protein tau were shown to cause familial FTD with parkinsonism linked to chromosome 17q21 (FTDP-17), a form of FTD characterized by tau-positive neuronal inclusions.

The majority of familial FTD cases do not show tauopathy, however, but display ubiquitin-immunoreactive neuronal inclusions that are mostly cytoplasmic but in some cases, nuclear. In multiple families, this form of FTD was linked to 17q21, the same region where the tau gene sits, but extensive searches yielded no mutations in that gene to account for the disease. That led several groups on an extensive search for mutations in other genes in a roughly 6-Mb critical region of 17q21. The Mayo researchers, working with collaborators from the University of British Columbia in Vancouver, Canada, and the University of Manchester in the U.K., focused on a large Canadian FTD family. After analyzing the coding sequences of 80 of the approximately 165 genes in the region, first authors Matt Baker, Ian Mackenzie, and Stuart Pickering-Brown hit pay dirt when they found an insertional mutation in the progranulin gene (PGRN).

Following the same strategy, first author Marc Cruts and the Van Broeckhoven team in Belgium ruled out MAPT mutations in a Dutch family, and then proceeded to identify a nonsense mutation in the progranulin gene. In all, the researchers identified 13 distinct progranulin deletions, insertions, and transitions in a total of nine families as well as in three unrelated patients. The mutations segregated with disease in families, and were never found among hundreds of unrelated controls tested. In a group of 43 Belgian patients with FTD, progranulin mutations were 3.5 times more frequent than tau mutations.

The progranulin mutations all introduced premature stop codons, and appeared to act as null alleles. The Mayo group showed that mutations resulted in nonsense-mediated RNA decay, and both groups documented lower levels of progranulin protein in lymphoblasts from affected family members.

In the brain, progranulin protein is present in cortical neurons and also in activated microglia in patients in FTD families, as well as in normal aged subjects and in people with Alzheimer disease. The presence of nuclear ubiquitin-positive inclusions appears especially associated with PGRN mutations, but neither those aggregates, nor the cytoplasmic inclusions showed any reactivity with progranulin antibodies. Their composition, therefore, remains an unsolved mystery.

Progranulin is widely expressed, and is involved in development, wound repair, and inflammation. Although the role of progranulin in neurons is unknown, the weight of evidence that PGRN haploinsufficiency causes FTD makes it clear that this factor is important for neuronal survival. Progranulin is known to activate signaling cascades including the MAP kinase and PI3 kinase pathways, both important for neuronal survival and function. On the flip side, overexpression of progranulin is involved in tumorigenesis, and high levels are found in glioblastomas.

Hutton and colleagues point out the similarity between progranulin and its role in FTD, and the secreted factor angiogenin, mutations in which have been linked to motor neuron loss in ALS (see ARF related news story). Angiogenin and progranulin have common functions, in that they both induce angiogenesis via vascular endothelial growth factor (VEGF), and tumorigenesis. Their deficiency may even result in a common neuropathology. Coauthors Ian Mackenzie and Howard Feldman showed previously that the ubiquitin-immunoreactive inclusions of FTD and motor neuron diseases display some similarities, suggesting they may spring from the same underlying events (Mackenzie and Feldman, 2005). The link of both factors to VEGF production, which itself has been shown to rescue motor neurons in a mouse model of ALS (see ARF related news story), opens up a world of new possibilities for further research and potential therapeutics.—Pat McCaffrey.

References:
Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wils H, Pirici D, Rademakers R, Vandenberghe R, Dermaut B, Martin J, van Duijn C, Peeters K, Sciot R, Santerns P, De Pooter T, Mattheijssens M, Van den Broeck M, Cuijt I, Vennekens K, De Deyn P, Kumar-Singh S, Van Broeckhoven C. Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature. 2006 July 16; [Early online publication]. Abstract

Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, Snowden J, Adamson J, Sadnovick AD, Rollinson S, Cannon A, Dwosh E, Neary D, Melquist S, Richardson A, Dickson D, Berger Z, Eriksen J, Robinson T, Zehr C, Diceky A, Crook R, McGowan E, Mann D, Boeve B, Feldman H, Hutton M. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature. 2006 July 16; [Early online publication]. Abstract