Progranulin mutations and amyotrophic lateral sclerosis or amyotrophic lateral sclerosis-frontotemporal dementia phenotypes

Johns Hopkins University, Baltimore, Maryland, United States
Journal of neurology, neurosurgery, and psychiatry (Impact Factor: 5.58). 08/2007; 78(7):754-6. DOI: 10.1136/jnnp.2006.109553
Source: PubMed

ABSTRACT Mutations in the progranulin (PGRN) gene were recently described as the cause of ubiquitin positive frontotemporal dementia (FTD). Clinical and pathological overlap between amyotrophic lateral sclerosis (ALS) and FTD prompted us to screen PGRN in patients with ALS and ALS-FTD.
The PGRN gene was sequenced in 272 cases of sporadic ALS, 40 cases of familial ALS and in 49 patients with ALS-FTD.
Missense changes were identified in an ALS-FTD patient (p.S120Y) and in a single case of limb onset sporadic ALS (p.T182M), although the pathogenicity of these variants remains unclear.
PGRN mutations are not a common cause of ALS phenotypes.

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Available from: Matthew Greenway, Aug 24, 2015
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    • "Overall, mutations of the microtubule associated phosphoprotein tau (MAPT) and the progranulin (PRGN) gene each account for 5–11% of total FTD cases [32–35]. Although associated with TDP-43 pathology , PGRN mutations are not usually identified in patients with familial ALS [36]. Mutations of the gene encoding for TDP-43 (TARBP), recognized as a cause of familial ALS, have also been identified in cases of FTD-ALS [37], and rarely in FTD [38]. "
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    ABSTRACT: Frontotemporal dementia (FTD) is an important cause of non-Alzheimer's dementia and is the second most common cause of young onset dementia. FTD presents with progressive changes in behavior and personality (behavioral variant FTD) or language deficits (also known as primary progressive aphasia), although both commonly coexist. Patients with progressive aphasia are subclassified according to the pattern of language deficits into those with progressive non-fluent aphasia (PNFA) and semantic dementia (SD). FTD is pathologically heterogeneous, both macroscopically and on a molecular level, with tau positive, TDP-43 positive, and FUS positive intraneuronal inclusions recognized on immunohistochemical analysis. TDP-43 positive inclusions are also a feature of amyotrophic lateral sclerosis pathology, corroborating the observation of overlapping clinical features between the two conditions and reaffirming the FTD-ALS disease spectrum. Most FTD cases are sporadic, but an important minority is inherited in an autosomal dominant fashion, most commonly due to MAPT or progranulin gene mutations. Familial clusters of FTD and amyotrophic lateral sclerosis are also recognized but poorly understood. This paper reviews the clinical phenotypes, assessment and treatment of FTD in light of recent pathological and genetic discoveries.
    Journal of Alzheimer's disease: JAD 04/2010; 21(2):349-60. DOI:10.3233/JAD-2010-091513 · 4.15 Impact Factor
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    • "The levels of progranulin in plasma have been suggested as a useful marker for early identification of a risk in asymptomatic subjects. We identified the p.S120Y change in a single case of limb onset sporadic ALS; the mutation has been previously reported in an ALS-FTD patient (Schymick et al., 2007a), and both patients share a common haplotype across the gene suggesting a shared common ancestor for this region of their genome. The identification of an identical mutation in a second individual diagnosed with a rare neurodegenerative disease increases the likelihood that this change is pathogenic. "
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    ABSTRACT: To analyze the contribution of progranulin (PGRN) to the etiopathogenesis of amyotrophic lateral sclerosis (ALS), we performed a PGRN gene screening in 146 Italian patients (12 familial cases) and evaluated the association of two common variants with risk of developing ALS in 239 sporadic cases (SALS). Progranulin mRNA and protein levels were measured in peripheral blood mononuclear cells and serum of a subset of these patients and controls. PGRN sequence analysis revealed a heterozygous change (p.S120Y), previously observed in an independent sporadic ALS-FTD patient. Haplotype analysis showed a conserved PGRN region among these two subjects consistent with possible common ancestor allele. Two non-coding polymorphisms were not associated to increased risk to develop ALS; mRNA and serum levels were not significantly different between cases and controls. Overall, our data argue against the hypothesis of progranulin as a major risk factor for motor neuron dysfunction, at least in Italian population. The p.S120Y variant may characterize rare patients with SALS, although its pathogenetic mechanism remains to be elucidated.
    Neurobiology of aging 08/2009; 32(6):1157-8. DOI:10.1016/j.neurobiolaging.2009.06.006 · 4.85 Impact Factor
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    • "Most of the PGRN mutations are non-sense mutations leading to non-sense-mediated mRNA decay and thus result in a loss of function because of haploinsufficiency (Baker et al. 2006). However, a few missense mutations have also been identified (Mukherjee et al. 2006; Schymick et al. 2007; van der Zee et al. 2007). These lead either to reduced secretion of PGRN or to a mislocalization of PGRN to the cytosol followed by its degradation (Mukherjee et al. 2008; Shankaran et al. 2008). "
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    ABSTRACT: Neuronal and glial deposition of misfolded, proteolytically processed, polyubiquitinated and abnormally phosphorylated C-terminal fragments (CTFs) of the TAR DNA binding protein-43 (TDP-43) is a pathological hallmark of frontotemporal lobar degeneration with ubiquitin positive inclusions (FTLD-U) and certain cases of amyotrophic lateral sclerosis. We demonstrate that TDP-43 can be proteolytically processed by caspases upon induction of apoptosis to a major 35 kDa and a minor 25 kDa CTF. These fragments are initially soluble, but over time they accumulate as insoluble and pathologically phosphorylated derivatives. However, proteolytic processing appears not to be absolutely required for the deposition of insoluble TDP-43 species, since a caspase resistant mutant of TDP-43 is also converted into insoluble species. Phosphorylation at S409/410 apparently occurs late during the conversion of soluble to insoluble TDP-43, suggesting that phosphorylation is not a prerequisite for aggregation. Loss of function of the progranulin (PGRN) gene causes FTLD-U with TDP-43 positive inclusions and has been suggested to lead to caspase activation and subsequent TDP-43 processing. However, siRNA-mediated knockdown of PGRN in cell culture as well as a PGRN gene knockout in mice failed to cause the formation of the disease characterizing CTFs of TDP-43. Our findings therefore suggest that caspase-mediated processing generates CTFs of similar biochemical properties as those occurring in nuclear and cytoplasmic deposits of FTLD-U patients independent of PGRN levels.
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