Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17

@article{Baker2006MutationsIP,
  title={Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17},
  author={Matt C. Baker and Ian R A Mackenzie and Stuart Pickering-Brown and Jennifer M Gass and Rosa Rademakers and Caroline Lindholm and Julie S. Snowden and Jennifer L. Adamson and A Dessa Sadovnick and Sara Rollinson and Ashley Cannon and Emily Dwosh and David Neary and Stacey Melquist and Anna M. T. Richardson and Dennis Dickson and Zdeněk Berger and Jason L. Eriksen and Todd Robinson and Cindy Zehr and Chad A Dickey and Richard J. P. Crook and Eileen M McGowan and David M A Mann and Bradley F. Boeve and Howard H Feldman and Michael L. Hutton},
  journal={Nature},
  year={2006},
  volume={442},
  pages={916-919}
}
Frontotemporal dementia (FTD) is the second most common cause of dementia in people under the age of 65 years. A large proportion of FTD patients (35–50%) have a family history of dementia, consistent with a strong genetic component to the disease. In 1998, mutations in the gene encoding the microtubule-associated protein tau (MAPT) were shown to cause familial FTD with parkinsonism linked to chromosome 17q21 (FTDP-17). The neuropathology of patients with defined MAPT mutations is characterized… 

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

It is demonstrated 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 tumorigenesis, and evidence that P GRN haploinsufficiency leads to neurodegeneration because of reduced PGRN-mediated neuronal survival is provided.

Progranulin gene mutations associated with frontotemporal dementia and progressive non-fluent aphasia.

A clinico-pathological investigation of two FTLD families with PGRN mutations is reported, for the first time, and provides compelling evidence for the link between FTD and PNFA, while raising the possibility of identifiable clinical differences between FTLD patients with MAPT and P GRN mutations.

The Genetics of Monogenic Frontotemporal Dementia

  • L. Takada
  • Biology
    Dementia & neuropsychologia
  • 2015
Since the identification of mutations in MAPT (microtubule-associated protein tau gene) in 1998, over 10 other genes have been associated with FTD spectrum disorders, discussed in this review.

The neuropathology of frontotemporal lobar degeneration caused by mutations in the progranulin gene.

It is suggested that FTD caused by PGRN mutations has a recognizable pathology with the most characteristic feature being ub-ir NII, which is similar to those with proven mutations.

Frontotemporal dementia in a large Swedish family is caused by a progranulin null mutation

The P GRN Gly35fs mutation causes frontotemporal dementia with variable clinical presentation in a large Swedish family, most likely through nonsense-mediated decay of mutant PGRN mRNA and resulting haploinsufficiency.

Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration.

Clinical examination of patients with PGRN mutations revealed highly variable onset ages with language dysfunction as a common presenting symptom, and neuropathological examination showed FTLD with ubiquitin-positive cytoplasmic and intranuclear inclusions in all P GRN mutation carriers.

Clinicopathologic correlation in PGRN mutations

PGRN mutations at 17q21 may occur in apparently sporadic frontotemporal lobar dementia with ubiquitinated inclusions cases and in cases presenting with either primary progressive aphasia or the behavioral variant of frontotmporal dementia.

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

The 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, highlighting the many similarities but also a few important differences.

A novel progranulin mutation associated with variable clinical presentation and tau, TDP43 and alpha-synuclein pathology.

A link between mutations in GRN and aggregation of tau, TDP43 and SNCA is suggested and this mutation alters splicing of exon 7 and results in reduced mRNA message in brain.

Autosomal Dominant Frontotemporal Lobar Degeneration: From Genotype to Phenotype

Next-generation sequencing approach allowed the identification of disease modifier genes such as common variants in the transmembrane protein 106b and other genes linked to rare cases of familial FTLD.
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References

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

It is demonstrated 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 tumorigenesis, and evidence that P GRN haploinsufficiency leads to neurodegeneration because of reduced PGRN-mediated neuronal survival is provided.

A family with tau-negative frontotemporal dementia and neuronal intranuclear inclusions linked to chromosome 17.

Detailed clinical and neuropathological findings in a new large, multigenerational family with autosomal dominant FTD and autopsy proven tau-negative, ub-ir neuronal cytoplasmic and intranuclear inclusions are described that is linked to a 19.06 cM region of chromosome 17q21 containing MAPt.

Familial frontotemporal dementia with ubiquitin-positive inclusions is linked to chromosome 17q21-22.

Pathological examination of the brains of two affected family members showed non-specific neuronal degeneration with dense cytoplasmic ubiquitin-positive inclusions in neurones of the second layer of the frontotemporal cortex and dentate gyrus of the hippocampus, the first report of ubiquitIn-positive, tau-negativeInclusions in an FTD family with significant linkage to chromosome 17q21-22.

Familial frontotemporal dementia with ubiquitin-positive, tau-negative inclusions

This family with autosomal dominant frontotemporal dementia (FTD) shows no tau expression in neurons, and some pathologic features are similar to those of several of the families included in descriptions of FTD with parkinsonism linked to chromosome 17, but the linkage to tau has been excluded.

Genomic architecture of human 17q21 linked to frontotemporal dementia uncovers a highly homologous family of low-copy repeats in the tau region.

Enterprise studies, short tandem repeat-based linkage disequilibrium (LD) and macro-restriction mapping, andnotation demonstrated that MAPT is surrounded by three highly homologous low-copy repeats (LCRs) in a region of 1.7 Mb, which predicts that other potentially more complex genomic rearrangements might be underlying FTDU-17.

Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17

Thirteen families have been described with an autosomal dominantly inherited dementia named frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), historically termed Pick's

Chromosome 17 and hereditary dementia

Evidence against linkage to D17S579 in the set of 60 families with late-onset FAD is presented, providing further evidence that the chromosome 17 gene is unlikely to be involved in the pathogenesis of typical AD.

Mapping of a disease locus for familial rapidly progressive frontotemporal dementia to chromosome 17q12-21.

The genetics of a Swedish family with an early-onset type of rapidly progressive FTD, associated with muscular rigidity and akinetic movements, and Sequencing of the translated exons of a strong candidate gene in the linked region of chromosome 17, the tau gene, failed to identify any mutations segregating with the disease.

Neuronal Intranuclear Inclusions Distinguish Familial FTD-MND Type from Sporadic Cases

Although intranuclear inclusions are most characteristic of families with pure FTD, they may also be found in some pedigrees with both FTD and MND, further supporting the hypothesis that FTD-MND type and M ND-dementia represent a clinicopathological spectrum of disease.

Frontotemporal dementia and parkinsonism linked to chromosome 17: A consensus conference

We held an international consensus conference on frontotemporal dementia, behavioral disturbances, and parkinsonism linked to chromosome 17 to determine whether these are homogeneous or heterogeneous