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Neurological Review |

Refining Frontotemporal Dementia With Parkinsonism Linked to Chromosome 17:  Introducing FTDP-17 (MAPT) and FTDP-17 (PGRN) FREE

Bradley F. Boeve, MD; Mike Hutton, PhD
[+] Author Affiliations

Author Affiliations:Divisions of Behavioral Neurology and Movement Disorders, Department of Neurology, Mayo Clinic, Rochester, Minnesota (Dr Boeve); Mayo Alzheimer's Disease Research Center, and Robert H. and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program of the Mayo Foundation, Rochester, Minnesota, and Jacksonville, Florida (Drs Boeve and Hutton); and Neurogenetics Laboratory, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida (Dr Hutton).


Section Editor: David E. Pleasure, MD

More Author Information
Arch Neurol. 2008;65(4):460-464. doi:10.1001/archneur.65.4.460.
Text Size: A A A
Published online

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 MAPTon 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 MAPTand 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.

Figures in this Article

Frontotemporal dementia with parkinsonism is one of the major degenerative dementia syndromes (Table 1), particularly for those who begin experiencing cognitive, behavioral, or motor changes before age 65 years. Advances in immunocytochemistry and molecular genetics have greatly expanded our knowledge of the disorders (and their associated dysfunctional proteins) that can manifest as dementia with or without parkinsonism (Table 2). No disease-altering treatment has been identified as yet for any of the neurodegenerative disorders that can manifest clinically as FTDP (Table 2). The development of potential therapies requires knowledge about the pathophysiology of the varying disorders. The identification of causative genes offers opportunities to quickly learn about the pathophysiologic processes involved in neurodegeneration, and drug testing can proceed relatively quickly using transgenic mouse models that are designed to mimic the human disease. Several groups of investigators have focused on families carrying mutations that cause FTDP.

Table Graphic Jump LocationTable 1. Major Cognitive Impairment and Dementia Syndromes

Table Graphic Jump LocationTable 2. Specific Neurodegenerative Disorders Manifesting as Dementia With or Without Parkinsonism and Their Associated Dysfunctional Proteins

The hunt for causative genes in FTDP was largely spearheaded by the first Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17 Consensus Conference in Ann Arbor in 1996, for which FTDP linked to chromosome 17 (FTDP-17) was the major focus.1Soon thereafter in 1998, mutations in MAPTwere identified.2During the 8 years since this discovery, 41 mutations in MAPThave been found,3and many other issues relating to FTDP-17 due to mutations in MAPThave been characterized (Table 3).4No sex predilection has been identified. The typical age of onset varies between 25 and 65 years. Penetrance appears to be close to 100%, though individuals living into old age without symptoms have been observed in families with at least 1 mutation (exon 10 + 16).2The duration of symptoms from onset to death is typically 3 to 10 years. Symptomatology usually involves executive dysfunction and altered personality and behavior, with aphasia and parkinsonism evolving in many individuals. Memory impairment occurs less frequently as the primary presenting feature, and visuospatial impairment and limb apraxia are quite rare. Motor neuron disease is also infrequent, though several cases have been reported. Most patients carry 1 or more of the syndromic diagnoses listed in Table 1, particularly frontotemporal dementia (FTD) with or without parkinsonism, progressive nonfluent aphasia, or primary progressive aphasia. Rarely, the syndromes of mild cognitive impairment, probable Alzheimer disease, semantic dementia, or corticobasal syndrome are manifested. Few cases have been diagnosed with amyotrophic lateral sclerosis (ALS), and there are no reports of patients with mutations in MAPTwho were diagnosed with posterior cortical atrophy or dementia with Lewy bodies. Over time, most patients develop other clinical features such that 2 or more syndromes can be applied, reflecting the progressively expanding involvement of other brain regions.5

Table Graphic Jump LocationTable 3. Comparison Between Neurodegenerative Characteristics Associated With Mutations in MAPTand PGRNGenes

Structural neuroimaging studies show frontal and/or temporal atrophy, either symmetric or asymmetric6; parenchymal signal changes on magnetic resonance imaging are either absent or very mild.7A similar topography of abnormalities is typically seen on single-photon emission computed tomography and positron emission tomography scans, often with basal ganglia and/or thalamic hypoperfusion or hypometabolism. Pathologically, cortical atrophy is as indicated on imaging studies, with the maximally affected cortical gyri sometimes described as having a “knife edge” appearance. Tau-positive inclusions in neurons (eg, neurofibrillary tangles, neuronal threads, and Pick bodies) and/or glia (eg, astrocytic plaques and oligodendroglial coiled bodies) are always present on histologic examination, sometimes accompanied by argyrophilic grains. These tau-positive inclusions are often in a distribution such that patients would be pathologically identified as having corticobasal degeneration, progressive supranuclear palsy, argyrophilic grain disease, or Pick disease if the presence of an MAPTmutation was not known.

The mutations presumably cause disease either through disrupting the alternative splicing of MAPTexon 10 and thereby altering the relative levels of tau isoforms with 4 or 3 microtubule binding repeats, or they directly decrease the ability of tau to bind to and promote microtubule assembly and/or increase tau-filament formation. No disease-altering treatments exist yet for the tauopathies, though kinase inhibitors and microtubule tau stabilizers have shown promise in in vitro and animal model studies.8,9

A significant minority of patients with FTDP-17—many of whom were the focus of discussion at the meeting in Ann Arbor in 1996—had no identifiable mutations in MAPT, nor did they have any tau-positive inclusions at autopsy.1013The recent identification of mutations in PGRNin all of these remaining chromosome 17–linked families and in many other kindreds (Figure)1427has now solved this decade-long conundrum, a few atypical FTDP phenotypes have been redefined, and an amazing freak of nature has been realized. The PGRNgene is only 1.7 Mb centromeric to MAPTon chromosome 17, demonstrating an intriguing example of how 2 apparently different genes can cause a very similar phenotype and reside so near to each other on the same chromosome.27

Place holder to copy figure label and caption
Figure.

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

Graphic Jump Location

With closer inspection, how similar are the clinical phenotypes associated with mutations in MAPTand PGRN? While our knowledge of the full spectrum of clinical, radiologic, and pathologic issues in FTDP associated with mutations in PGRNis still evolving, interesting findings have already emerged that allow comparisonsbetween MAPT's and PGRN's mutation-associated characteristics (based on published findings to date and unpublished data from our group) (Table 3). The frequency of mutations in PGRNin FTD series is similar to that in MAPT.18With at least 35 mutations identified to date,3almost as many mutations in PGRNhave been discovered in less than 1 year than in the 8 years since the initial identification of mutations in MAPT. The mode of inheritance follows an autosomal dominant pattern but with reduced penetrance (only 90% of carriers develop symptoms by age 70 years).18There are multiple known PGRNmutation carriers who are asymptomatic in their 70s, and at least 1 known affected individual developed symptoms after age 80 years. The clinical features and particularly the syndromic diagnoses have been more variable than in MAPTmutation carriers, with not only behavioral and cognitive features commonly present, but also memory impairment, limb apraxia, parkinsonism, and visuospatial dysfunction, leading to cases being diagnosed with mild cognitive impairment, Alzheimer disease, Parkinson disease, Parkinson disease with dementia, and dementia with Lewy bodies in addition to FTD with or without parkinsonism and 1 of the progressive aphasia syndromes.25The diagnosis of corticobasal syndrome has also been particularly frequent in the cases reported thus far, while no patient with a definite pathogenic PGRNmutation has been reported to date with an ALS phenotype.

As one would expect, based on the clinical features of apraxia and visuospatial dysfunction, greater parietal involvement is clearly present in many PGRNmutation cases, which is also reflected on imaging and pathologic studies. In some cases, rather striking signal changes on magnetic resonance imaging are present,25which is rarely seen in MAPTmutation carriers. Another curious observation is the tendency in some kindreds for the same cerebral hemisphere to be maximally involved in most or all affected members of a family, such as a progressive aphasia syndrome with maximal left hemisphere involvement22,26,28and the corticobasal syndrome with or without FTD features with maximal right hemisphere involvement25,29; to our knowledge, this tendency has not been noted among any kindreds with MAPTmutations.

On histologic examination, the consistent finding is FTLD with ubiquitin-positive inclusions with neuronal intranuclear inclusions.14,1618,2026Immunostaining directed against progranulin stain normal structures within neurons and activated microglia. However, the ubiquitinated inclusions are not progranulin immunoreactive; rather, transactive response DNA–binding protein 43 was very recently discovered to be a major ubiquitinated protein in both neuronal cytoplasmic and intranuclear inclusions in PGRNmutation cases.30Moreover, transactive response DNA–binding protein 43 is also present in neuronal ubiquitin-positive inclusions in FTLD with ubiquitin-positive inclusions, FTLD with motor neuron disease, and idiopathic ALS.31

Also contrasting with MAPTis the mechanism of disease with PGRNmutations—all PGRNmutations identified thus far create functional null alleles that cause a partial reduction in progranulin production or haploinsufficiency.14,16,18This disease mechanism may allow a more straightforward approach for treatment by either replacing progranulin or using drugs to increase production or secretion of progranulin from the remaining normal PGRNallele.

The net effect of 2 genes linked not only by proximity but also by most overlapping and expanding features requires refinements in our conceptual framework and nomenclature in FTDP. An obvious solution to this problem is to simply refine the term by including reference to the genetic cause of the disease in each case, and thus FTDP-17 could be subdivided into FTDP-17 (MAPT) and FTDP-17 (PGRN). This approach has the advantage of employing a now widely used, if not always completely appropriate, clinical terminology, refining it to reflect that ultimately these conditions are defined by their genetics rather than their clinical or pathological phenotypes. The scientific community has clearly just begun to expand the characterization and refine the nomenclature of familial disorders linked to chromosome 17.

Correspondence:Bradley F. Boeve, MD, Department of Neurology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (bboeve@mayo.edu).

Accepted for Publication:January 14, 2007.

Author Contributions:Study concept and design: Boeve and Hutton. Acquisition of data: Boeve and Hutton. Analysis and interpretation of data: Boeve and Hutton. Drafting of the manuscript: Boeve and Hutton. Administrative, technical, and material support: Boeve and Hutton.

Financial Disclosure:None reported.

Funding/Support:This study was supported by grants AG06786, AG16574, AG11378, and AG07216 from the National Institute on Aging; by the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program of the Mayo Foundation; and by the Fund for Scientific Research–Flanders.

Additional Contributions:We thank our many collaborators within and outside the Mayo Foundation, particularly Rosa Rademakers, PhD, for her critical review of this paper, and her and Matt Baker's assistance in providing the sequence chromatograms for Figure 1. We thank the staff of the Mayo Clinic Alzheimer's Disease Research Center for their assistance in characterizing participants, and we particularly thank the members of the many kindreds with MAPTand PGRNmutations for participating in neurodegenerative disease research.

Foster  NLWilhelmsen  KSima  AJones  MZD'Amato  CJGilman  S Frontotemporal dementia and parkinsonism linked to chromosome 17: a consensus conference. Ann Neurol 1997;41 (6) 706- 715
PubMed
Hutton  MLendon  CLRizzu  P  et al.  Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 1998;393 (6686) 702- 705
PubMed
 Alzheimer Disease & Frontotemporal Dementia Mutation Database. http://www.molgen.ua.ac.be/FTDmutations/. Accessed February 14, 2007
Poorkaj  PGrossman  MSteinbart  E  et al.  Frequency of tau gene mutations in familial and sporadic cases of non-Alzheimer dementia. Arch Neurol 2001;58 (3) 383- 387
PubMed
Kertesz  A Pick's complex and FTDP-17. Mov Disord 2003;18 ((suppl 6)) S57- S62
PubMed
Boeve  BFTremont-Lukats  IWaclawik  A  et al.  Longitudinal characterization of two siblings with frontotemporal dementia and parkinsonism linked to chromosome 17 associated with the S305N tau mutation. Brain 2005;128 (pt 4) 752- 772
PubMed
Frank  ARWszolek  ZKJack  CR  JrBoeve  BF Distinctive MRI findings in pallidopontonigral degeneration (PPND). Neurology 2007;68 (8) 620- 621
PubMed
Noble  WPlanel  EZehr  C  et al.  Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc Natl Acad Sci U S A 2005;102 (19) 6990- 6995
PubMed
Zhang  BMaiti  AShively  S  et al.  Microtubule-binding drugs offset tau sequestration by stabilizing microtubules and reversing fast axonal transport deficits in a tauopathy model. Proc Natl Acad Sci U S A 2005;102 (1) 227- 231
PubMed
Lendon  CLLynch  TNorton  J  et al.  Hereditary dysphasic disinhibition dementia: a frontotemporal dementia linked to 17q21-22. Neurology 1998;50 (6) 1546- 1555
PubMed
Rademakers  RCruts  MDermaut  B  et al.  Tau negative frontal lobe dementia at 17q21: significant finemapping of the candidate region to a 4.8 cM interval. Mol Psychiatry 2002;7 (10) 1064- 1074
PubMed
van der Zee  JRademakers  REngelborghs  S  et al.  A Belgian ancestral haplotype harbours a highly prevalent mutation for 17q21-linked tau-negative FTLD. Brain 2006;129 (pt 4) 841- 852
PubMed
Mackenzie  IRBaker  MWest  G  et al.  A family with tau-negative frontotemporal dementia and neuronal intranuclear inclusions linked to chromosome 17. Brain 2006;129 (pt 4) 853- 867
PubMed
Baker  MMackenzie  IPickering-Brown  S  et al.  Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 2006;442 (7105) 916- 919
PubMed
Benussi  LBinetti  GSina  E  et al.  A novel deletion in progranulin gene is associated with FTDP-17 and CBS [published online ahead of print December 5, 2006]. Neurobiol Aging 2008;29 (3) 427- 435
PubMed10.1016/j.neurobiolaging.2006.10.028
Boeve  BFBaker  MDickson  D  et al.  Frontotemporal dementia and parkinsonism associated with the IVS1+1G->A mutation in progranulin: a clinicopathologic study. Brain 2006;129 (pt 11) 3103- 3114
PubMed
Cruts  MGijselinck  Ivan der Zee  J  et al.  Null mutations in progranulin cause ubiquitin positive frontotemporal dementia linked to chromosome 17q21. Nature 2006;442 (7105) 920- 924
PubMed
Gass  JCannon  AMackenzie  I  et al.  Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. Hum Mol Genet 2006;15 (20) 2988- 3001
PubMed
Huey  EDGrafman  JWassermann  EM  et al.  Characteristics of frontotemporal dementia patients with a Progranulin mutation. Ann Neurol 2006;60 (3) 374- 380
PubMed
Mackenzie  IRBaker  MPickering-Brown  S  et al.  The neuropathology of frontotemporal lobar degeneration caused by mutations in the progranulin gene. Brain 2006;129 (pt 11) 3081- 3090
PubMed
Masellis  MMomeni  PMeschino  W  et al.  Novel splicing mutation in the progranulin gene causing familial corticobasal syndrome. Brain 2006;129 (pt 11) 3115- 3123
PubMed
Mukherjee  OPastor  PCairns  NJ  et al.  HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions caused by a missense mutation in the signal peptide of progranulin. Ann Neurol 2006;60 (3) 314- 322
PubMed
Pickering-Brown  SMBaker  MGass  J  et al.  Mutations in progranulin explain atypical phenotypes with variants in MAPT. Brain 2006;129 (pt 11) 3124- 3126
PubMed
Snowden  JSPickering-Brown  SMackenzie  I  et al.  Progranulin gene mutations associated with frontotemporal dementia and progressive non-fluent aphasia. Brain 2006;129 (pt 11) 3091- 3102
PubMed
Kelley  BJHaidar  WBoeve  BF  et al.  Prominent phenotypic variability associated with mutations in Progranulin [published online ahead of print October 18, 2007]. Neurobiol Aging
PubMed10.1016/j.neurobiolaging.2007.08.022
Mesulam  MJohnson  NKrefft  T  et al.  Progranulin mutations in primary progressive aphasia: the PPA1 and PPA3 families. Arch Neurol 2007;64 (1) 43- 47
PubMed
Rosenberg  RN Progranulin and tau gene mutations both as cause for dementia: 17q21 finally defined. Arch Neurol 2007;64 (1) 18- 19
PubMed
Krefft  TAGraff-Radford  NDickson  D  et al.  Familial primary progressive aphasia. Alzheimer Dis Assoc Disord 2003;17 (2) 106- 112
PubMed
Boeve  BFMaraganore  DMParisi  JE  et al.  Corticobasal degeneration and frontotemporal dementia presentations in a kindred with nonspecific histopathology. Dement Geriatr Cogn Disord 2002;13 (2) 80- 90
PubMed
Josephs  KAAhmed  ZKatsuse  O  et al.  Neuropathologic features of frontotemporal lobar degeneration with ubiquitin-positive inclusions with progranulin gene (PGRN) mutations. J Neuropathol Exp Neurol 2007;66 (2) 142- 151
PubMed
Neumann  MSampathu  DKwong  L  et al.  Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 2006;314 (5796) 130- 133
PubMed

Figures

Place holder to copy figure label and caption
Figure.

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

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Major Cognitive Impairment and Dementia Syndromes
Table Graphic Jump LocationTable 2. Specific Neurodegenerative Disorders Manifesting as Dementia With or Without Parkinsonism and Their Associated Dysfunctional Proteins
Table Graphic Jump LocationTable 3. Comparison Between Neurodegenerative Characteristics Associated With Mutations in MAPTand PGRNGenes

References

Foster  NLWilhelmsen  KSima  AJones  MZD'Amato  CJGilman  S Frontotemporal dementia and parkinsonism linked to chromosome 17: a consensus conference. Ann Neurol 1997;41 (6) 706- 715
PubMed
Hutton  MLendon  CLRizzu  P  et al.  Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 1998;393 (6686) 702- 705
PubMed
 Alzheimer Disease & Frontotemporal Dementia Mutation Database. http://www.molgen.ua.ac.be/FTDmutations/. Accessed February 14, 2007
Poorkaj  PGrossman  MSteinbart  E  et al.  Frequency of tau gene mutations in familial and sporadic cases of non-Alzheimer dementia. Arch Neurol 2001;58 (3) 383- 387
PubMed
Kertesz  A Pick's complex and FTDP-17. Mov Disord 2003;18 ((suppl 6)) S57- S62
PubMed
Boeve  BFTremont-Lukats  IWaclawik  A  et al.  Longitudinal characterization of two siblings with frontotemporal dementia and parkinsonism linked to chromosome 17 associated with the S305N tau mutation. Brain 2005;128 (pt 4) 752- 772
PubMed
Frank  ARWszolek  ZKJack  CR  JrBoeve  BF Distinctive MRI findings in pallidopontonigral degeneration (PPND). Neurology 2007;68 (8) 620- 621
PubMed
Noble  WPlanel  EZehr  C  et al.  Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc Natl Acad Sci U S A 2005;102 (19) 6990- 6995
PubMed
Zhang  BMaiti  AShively  S  et al.  Microtubule-binding drugs offset tau sequestration by stabilizing microtubules and reversing fast axonal transport deficits in a tauopathy model. Proc Natl Acad Sci U S A 2005;102 (1) 227- 231
PubMed
Lendon  CLLynch  TNorton  J  et al.  Hereditary dysphasic disinhibition dementia: a frontotemporal dementia linked to 17q21-22. Neurology 1998;50 (6) 1546- 1555
PubMed
Rademakers  RCruts  MDermaut  B  et al.  Tau negative frontal lobe dementia at 17q21: significant finemapping of the candidate region to a 4.8 cM interval. Mol Psychiatry 2002;7 (10) 1064- 1074
PubMed
van der Zee  JRademakers  REngelborghs  S  et al.  A Belgian ancestral haplotype harbours a highly prevalent mutation for 17q21-linked tau-negative FTLD. Brain 2006;129 (pt 4) 841- 852
PubMed
Mackenzie  IRBaker  MWest  G  et al.  A family with tau-negative frontotemporal dementia and neuronal intranuclear inclusions linked to chromosome 17. Brain 2006;129 (pt 4) 853- 867
PubMed
Baker  MMackenzie  IPickering-Brown  S  et al.  Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 2006;442 (7105) 916- 919
PubMed
Benussi  LBinetti  GSina  E  et al.  A novel deletion in progranulin gene is associated with FTDP-17 and CBS [published online ahead of print December 5, 2006]. Neurobiol Aging 2008;29 (3) 427- 435
PubMed10.1016/j.neurobiolaging.2006.10.028
Boeve  BFBaker  MDickson  D  et al.  Frontotemporal dementia and parkinsonism associated with the IVS1+1G->A mutation in progranulin: a clinicopathologic study. Brain 2006;129 (pt 11) 3103- 3114
PubMed
Cruts  MGijselinck  Ivan der Zee  J  et al.  Null mutations in progranulin cause ubiquitin positive frontotemporal dementia linked to chromosome 17q21. Nature 2006;442 (7105) 920- 924
PubMed
Gass  JCannon  AMackenzie  I  et al.  Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. Hum Mol Genet 2006;15 (20) 2988- 3001
PubMed
Huey  EDGrafman  JWassermann  EM  et al.  Characteristics of frontotemporal dementia patients with a Progranulin mutation. Ann Neurol 2006;60 (3) 374- 380
PubMed
Mackenzie  IRBaker  MPickering-Brown  S  et al.  The neuropathology of frontotemporal lobar degeneration caused by mutations in the progranulin gene. Brain 2006;129 (pt 11) 3081- 3090
PubMed
Masellis  MMomeni  PMeschino  W  et al.  Novel splicing mutation in the progranulin gene causing familial corticobasal syndrome. Brain 2006;129 (pt 11) 3115- 3123
PubMed
Mukherjee  OPastor  PCairns  NJ  et al.  HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions caused by a missense mutation in the signal peptide of progranulin. Ann Neurol 2006;60 (3) 314- 322
PubMed
Pickering-Brown  SMBaker  MGass  J  et al.  Mutations in progranulin explain atypical phenotypes with variants in MAPT. Brain 2006;129 (pt 11) 3124- 3126
PubMed
Snowden  JSPickering-Brown  SMackenzie  I  et al.  Progranulin gene mutations associated with frontotemporal dementia and progressive non-fluent aphasia. Brain 2006;129 (pt 11) 3091- 3102
PubMed
Kelley  BJHaidar  WBoeve  BF  et al.  Prominent phenotypic variability associated with mutations in Progranulin [published online ahead of print October 18, 2007]. Neurobiol Aging
PubMed10.1016/j.neurobiolaging.2007.08.022
Mesulam  MJohnson  NKrefft  T  et al.  Progranulin mutations in primary progressive aphasia: the PPA1 and PPA3 families. Arch Neurol 2007;64 (1) 43- 47
PubMed
Rosenberg  RN Progranulin and tau gene mutations both as cause for dementia: 17q21 finally defined. Arch Neurol 2007;64 (1) 18- 19
PubMed
Krefft  TAGraff-Radford  NDickson  D  et al.  Familial primary progressive aphasia. Alzheimer Dis Assoc Disord 2003;17 (2) 106- 112
PubMed
Boeve  BFMaraganore  DMParisi  JE  et al.  Corticobasal degeneration and frontotemporal dementia presentations in a kindred with nonspecific histopathology. Dement Geriatr Cogn Disord 2002;13 (2) 80- 90
PubMed
Josephs  KAAhmed  ZKatsuse  O  et al.  Neuropathologic features of frontotemporal lobar degeneration with ubiquitin-positive inclusions with progranulin gene (PGRN) mutations. J Neuropathol Exp Neurol 2007;66 (2) 142- 151
PubMed
Neumann  MSampathu  DKwong  L  et al.  Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 2006;314 (5796) 130- 133
PubMed

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