Alzheimer and Parkinson Diagnoses in Progranulin Null Mutation Carriers in an Extended Founder Family

University of Antwerp, Antwerpen, Flemish, Belgium
JAMA Neurology (Impact Factor: 7.42). 10/2007; 64(10):1436-46. DOI: 10.1001/archneur.64.10.1436
Source: PubMed


Progranulin gene (PGRN) haploinsufficiency was recently associated with ubiquitin-positive frontotemporal lobar degeneration linked to chromosome 17q21 (FTLDU-17).
To assess whether PGRN genetic variability contributed to other common neurodegenerative brain diseases, such as Alzheimer disease (AD) or Parkinson disease (PD).
Mutation analysis of PGRN.
Memory Clinic of the Middelheim General Hospital. Patients We analyzed 666 Belgian patients with AD and 255 with PD.
Results of PGRN sequencing, PGRN transcript analysis, short tandem repeat genotyping, and neuropathologic analysis.
We identified 2 patients with AD and 1 patient with PD who carried the null mutation IVS0 + 5G>C, which we reported earlier in an extensively characterized Belgian founder family, DR8, segregating FTLDU. Postmortem pathologic diagnosis of the patient with PD revealed both FTLDU and Lewy body pathologic features. In addition, we identified in PGRN only 1 other null mutation, the nonsense mutation p.Arg535X, in 1 patient with probable AD. However, in vitro analysis predicted a PGRN C-truncated protein, although it remains to be elucidated if this shortened transcript leads to haploinsufficiency.
Our mutation data indicated that null mutations are rare in patients with AD (3/666 = 0.45%) and PD (1/255 = 0.39%). Also, AD and PD clinical diagnoses in patients who carry PGRN null mutations likely result from etiologic heterogeneity rather than PGRN haploinsufficiency.

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Available from: Nathalie Brouwers, Aug 14, 2014
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    • "HEK 293FT and microglia BV-2 cells were maintained in DMEM Glutamax cell culture media (Life Technologies), supplemented with 10% fetal calf serum (Sigma Aldrich) and non-essential amino acids (Life Technologies). Epstein Barr virus transformed lymphoblast cells [12,59] were cultured in RPMI 1640 medium (Life Technologies), supplemented with 10% fetal calf serum (Sigma Aldrich) and glutamine (Life Technologies). 5 × 105 cells per ml were seeded and treated with 0.5 μM (LCLs) or 0.13 μM (BV-2) 5-aza-2′-deoxycytidine (DAC, Sigma Aldrich), dissolved in DMSO. Due to the low half-life of DAC, the cell culture media and DAC was replaced daily. "
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    ABSTRACT: Background Frontotemporal lobar degeneration (FTLD) is a heterogeneous group of neurodegenerative diseases associated with personality changes and progressive dementia. Loss-of-function mutations in the growth factor progranulin (GRN) cause autosomal dominant FTLD, but so far the pathomechanism of sporadic FTLD is unclear. Results We analyzed whether DNA methylation in the GRN core promoter restricts GRN expression and, thus, might promote FTLD in the absence of GRN mutations. GRN expression in human lymphoblast cell lines is negatively correlated with methylation at several CpG units within the GRN promoter. Chronic treatment with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (DAC) strongly induces GRN mRNA and protein levels. In a reporter assay, CpG methylation blocks transcriptional activity of the GRN core promoter. In brains of FTLD patients several CpG units in the GRN promoter are significantly hypermethylated compared to age-matched healthy controls, Alzheimer and Parkinson patients. These CpG motifs are critical for GRN promoter activity in reporter assays. Furthermore, DNA methyltransferase 3a (DNMT3a) is upregulated in FTLD patients and overexpression of DNMT3a reduces GRN promoter activity and expression. Conclusion These data suggest that altered DNA methylation is a novel pathomechanism for FTLD that is potentially amenable to targeted pharmacotherapy.
    05/2013; 1(1). DOI:10.1186/2051-5960-1-16
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    • "Among the missense mutations studied, two (p.P248L and p.R432C) were reported to lead to decreased secretion, and one (p.C139R) reduces PGRN production, stability and patient plasma levels [7,25,32]. p.S120Y, is unlikely to be pathogenic since it is found in control patients [37,38] was found to promote neurite outgrowth similar to WT rPGRN. In contrast, rPGRN with p.C139R, p.R432C or p.P248L mutations did not stimulate neurite outgrowth, suggesting that these mutations adversely affect PGRN function and may be pathogenic, which would be consistent with previous genetic studies [39,40]. "
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    ABSTRACT: Progranulin (PGRN), a widely secreted growth factor, is involved in multiple biological functions, and mutations located within the PGRN gene (GRN) are a major cause of frontotemporal lobar degeneration with TDP-43-positive inclusions (FLTD-TDP). In light of recent reports suggesting PGRN functions as a protective neurotrophic factor and that sortilin (SORT1) is a neuronal receptor for PGRN, we used a Sort1-deficient (Sort1 −/− ) murine primary hippocampal neuron model to investigate whether PGRN’s neurotrophic effects are dependent on SORT1. We sought to elucidate this relationship to determine what role SORT1, as a regulator of PGRN levels, plays in modulating PGRN’s neurotrophic effects. As the first group to evaluate the effect of PGRN loss in Grn knockout primary neuronal cultures, we show neurite outgrowth and branching are significantly decreased in Grn −/− neurons compared to wild-type (WT) neurons. More importantly, we also demonstrate that PGRN overexpression can rescue this phenotype. However, the recovery in outgrowth is not observed following treatment with recombinant PGRN harboring missense mutations p.C139R, p.P248L or p.R432C, indicating that these mutations adversely affect the neurotrophic properties of PGRN. In addition, we also present evidence that cleavage of full-length PGRN into granulin peptides is required for increased neuronal outgrowth, suggesting that the neurotrophic functions of PGRN are contained within certain granulins. To further characterize the mechanism by which PGRN impacts neuronal morphology, we assessed the involvement of SORT1. We demonstrate that PGRN induced-outgrowth occurs in the absence of SORT1 in Sort1 −/− cultures. We demonstrate that loss of PGRN impairs proper neurite outgrowth and branching, and that exogenous PGRN alleviates this impairment. Furthermore, we determined that exogenous PGRN induces outgrowth independent of SORT1, suggesting another receptor(s) is involved in PGRN induced neuronal outgrowth.
    Molecular Neurodegeneration 07/2012; 7(1):33. DOI:10.1186/1750-1326-7-33 · 6.56 Impact Factor
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    • "Only two subjects have been described having both PD and GRN mutations, one with neuropathological confirmation of both FTLD ubiquitin-positive inclusions and Lewy body pathologic features [11] [30]. Data from GRN sequencing screening of PD patients do not support a major role of GRN in the genetic etiology of PD [11] [31]. Nowadays, we cannot discern if this patient's clinical phenotype is related to the GRN mutation or to coincidental idiopathic PD. "
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    ABSTRACT: Progranulin gene (GRN) mutations cause frontotemporal lobar degeneration (FTLD) with TDP43-positive inclusions, although its clinical phenotype is heterogeneous and includes patients classified as behavioral variant-FTLD (bvFTLD), progressive non-fluent aphasia (PNFA), corticobasal syndrome, Alzheimer's disease (AD), or Parkinson's disease (PD). Our main objective was to study if low serum progranulin protein (PGRN) levels may detect GRN mutations in a Spanish cohort of patients with FTLD or AD. Serum PGRN levels were measured in 112 subjects: 17 bvFTLD, 20 PNFA, 4 semantic dementia, 34 sporadic AD, 9 AD-PSEN1 mutation carriers, 10 presymptomatic-PSEN1 mutation carriers, and 18 control individuals. We detected 5 patients with PGRN levels below 94 ng/mL: two of them had a clinical diagnosis of bvFTLD, two of PNFA, and one of AD. The screening for GRN mutations detected two probable pathogenic mutations (p.C366fsX1 and a new mutation: p.V279GfsX5) in three patients and one mutation of unclear pathogenic nature (p.C139R) in one patient. The other patient showed a normal GRN sequence but carried a PRNP gene mutation. We observed no differences in serum PGRN levels between controls (mean = 145.5 ng/mL, SD = 28.5) and the other neurodegenerative diseases, except for the carriers of pathological GRN gene mutations (mean = 50.5 ng/mL, SD = 21.2). Null GRN mutation carriers also showed lower serum PGRN levels than the patient who was a carrier of p.C139R (92.3 ng/mL) and the one who was a carrier of the PRNP mutation (76.9 ng/mL). In conclusion, we detected GRN null mutations in patients with severely reduced serum PGRN levels, but not in patients with slightly reduced PGRN levels.
    Journal of Alzheimer's disease: JAD 05/2012; 31(3):581-91. DOI:10.3233/JAD-2012-112120 · 4.15 Impact Factor
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