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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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    • "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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    • "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.
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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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