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Plasma progranulin levels predict progranulin mutation status in frontotemporal dementia patients and asymptomatic family members.

Finch N, Baker M, Crook R, Swanson K, Kuntz K, Surtees R, Bisceglio G, Rovelet-Lecrux A, Boeve B, Petersen RC, Dickson DW, Younkin SG, Deramecourt V, Crook J, Graff-Radford NR, Rademakers R - Brain (2009)

Bottom Line: The clinical presentation associated with GRN mutations is heterogeneous and may include clinical probable Alzheimer's disease.The approximately 75% reduction in full-length GRN, suggests an unbalanced GRN metabolism in loss-of-function mutation carriers whereby more GRN is processed into granulins.We propose that plasma GRN levels could be used as a reliable and inexpensive tool to identify all GRN mutation carriers in early-onset dementia populations and asymptomatic at-risk individuals.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.

ABSTRACT
Mutations in the progranulin gene (GRN) are an important cause of frontotemporal lobar degeneration (FTLD) with ubiquitin and TAR DNA-binding protein 43 (TDP43)-positive pathology. The clinical presentation associated with GRN mutations is heterogeneous and may include clinical probable Alzheimer's disease. All GRN mutations identified thus far cause disease through a uniform disease mechanism, i.e. the loss of functional GRN or haploinsufficiency. To determine if expression of GRN in plasma could predict GRN mutation status and could be used as a biological marker, we optimized a GRN ELISA and studied plasma samples of a consecutive clinical FTLD series of 219 patients, 70 control individuals, 72 early-onset probable Alzheimer's disease patients and nine symptomatic and 18 asymptomatic relatives of GRN mutation families. All FTLD patients with GRN loss-of-function mutations showed significantly reduced levels of GRN in plasma to about one third of the levels observed in non-GRN carriers and control individuals (P < 0.001). No overlap in distributions of GRN levels was observed between the eight GRN loss-of-function mutation carriers (range: 53-94 ng/ml) and 191 non-GRN mutation carriers (range: 115-386 ng/ml). Similar low levels of GRN were identified in asymptomatic GRN mutation carriers. Importantly, ELISA analyses also identified one probable Alzheimer's disease patient (1.4%) carrying a loss-of-function mutation in GRN. Biochemical analyses further showed that the GRN ELISA only detects full-length GRN, no intermediate granulin fragments. This study demonstrates that using a GRN ELISA in plasma, pathogenic GRN mutations can be accurately detected in symptomatic and asymptomatic carriers. The approximately 75% reduction in full-length GRN, suggests an unbalanced GRN metabolism in loss-of-function mutation carriers whereby more GRN is processed into granulins. We propose that plasma GRN levels could be used as a reliable and inexpensive tool to identify all GRN mutation carriers in early-onset dementia populations and asymptomatic at-risk individuals.

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Specific plasma GRN levels in all types of GRN mutations. GRN expression is plotted for each patient with FTLD from our cohort carrying a GRN mutation. Black bars represent patients with FTLD carrying pathogenic GRN loss-of-function mutations; grey bars represent patients with FTLD carrying GRN mutations with unknown significance. The dashed line is the cut-off value for pathogenic GRN loss-of-function mutations based on the complete FTLD series and the black line indicates the minimum GRN expression identified in our control cohort (Fig. 1). Missense mutations p.R19W and p.C139R show GRN levels below the range detected in control individuals and may induce a partial loss of GRN function.
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Figure 2: Specific plasma GRN levels in all types of GRN mutations. GRN expression is plotted for each patient with FTLD from our cohort carrying a GRN mutation. Black bars represent patients with FTLD carrying pathogenic GRN loss-of-function mutations; grey bars represent patients with FTLD carrying GRN mutations with unknown significance. The dashed line is the cut-off value for pathogenic GRN loss-of-function mutations based on the complete FTLD series and the black line indicates the minimum GRN expression identified in our control cohort (Fig. 1). Missense mutations p.R19W and p.C139R show GRN levels below the range detected in control individuals and may induce a partial loss of GRN function.

Mentions: We then determined whether the levels of GRN in plasma could be used to distinguish GRN loss-of-function mutation carriers from non-GRN carriers in our FTLD series. Using a GRN ELISA we analysed a subset of 207 patients with FTLD from our consecutive cohort with plasma availability, including seven loss-of-function GRN mutation carriers and patient NGR247 carrying the partial GRN deletion, p.A472_Q548del. A significant reduction in GRN levels was observed in all patients carrying GRN loss-of-function mutations to about one third of the level observed in non-GRN carriers (Fig. 1; Table 2). GRN levels ranged from 53 to 94 ng/ml (mean value ± SD: 68 ± 16 ng/ml) in mutation carriers, while non-GRN carriers showed levels from 115 to 386 ng/ml (mean value ± SD: 220 ± 47 ng/ml). Interestingly, GRN levels were variable among GRN mutation carriers with slightly higher expression in NGR019 (88 ng/ml) carrying the p.A9D mutation in the signal peptide sequence and NGR247 (94 ng/ml) carrying p.A472_Q548del, compared to the typical frameshift and nonsense mutation carriers (Fig. 2). Based on our data alone, any cut-off value between 94 and 115 ng/ml is associated with crude estimates of both sensitivity and specificity of 100%. By assuming normality of GRN levels after a square root transformation, we were able to explore continuous estimates of sensitivity and specificity with different cut-off values (Table 3). A cut-off value of 112 ng/ml maximized the average of the estimates of sensitivity and specificity. GRN levels in 70 control individuals ranged from 138 to 376 ng/ml (mean value ± SD: 228 ± 50 ng/ml) comparable to patients with FTLD without GRN mutations (Fig. 1). As expected, normal GRN expression (259 ng/ml) was observed in our MAPT mutation carrier.Figure 1


Plasma progranulin levels predict progranulin mutation status in frontotemporal dementia patients and asymptomatic family members.

Finch N, Baker M, Crook R, Swanson K, Kuntz K, Surtees R, Bisceglio G, Rovelet-Lecrux A, Boeve B, Petersen RC, Dickson DW, Younkin SG, Deramecourt V, Crook J, Graff-Radford NR, Rademakers R - Brain (2009)

Specific plasma GRN levels in all types of GRN mutations. GRN expression is plotted for each patient with FTLD from our cohort carrying a GRN mutation. Black bars represent patients with FTLD carrying pathogenic GRN loss-of-function mutations; grey bars represent patients with FTLD carrying GRN mutations with unknown significance. The dashed line is the cut-off value for pathogenic GRN loss-of-function mutations based on the complete FTLD series and the black line indicates the minimum GRN expression identified in our control cohort (Fig. 1). Missense mutations p.R19W and p.C139R show GRN levels below the range detected in control individuals and may induce a partial loss of GRN function.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2664450&req=5

Figure 2: Specific plasma GRN levels in all types of GRN mutations. GRN expression is plotted for each patient with FTLD from our cohort carrying a GRN mutation. Black bars represent patients with FTLD carrying pathogenic GRN loss-of-function mutations; grey bars represent patients with FTLD carrying GRN mutations with unknown significance. The dashed line is the cut-off value for pathogenic GRN loss-of-function mutations based on the complete FTLD series and the black line indicates the minimum GRN expression identified in our control cohort (Fig. 1). Missense mutations p.R19W and p.C139R show GRN levels below the range detected in control individuals and may induce a partial loss of GRN function.
Mentions: We then determined whether the levels of GRN in plasma could be used to distinguish GRN loss-of-function mutation carriers from non-GRN carriers in our FTLD series. Using a GRN ELISA we analysed a subset of 207 patients with FTLD from our consecutive cohort with plasma availability, including seven loss-of-function GRN mutation carriers and patient NGR247 carrying the partial GRN deletion, p.A472_Q548del. A significant reduction in GRN levels was observed in all patients carrying GRN loss-of-function mutations to about one third of the level observed in non-GRN carriers (Fig. 1; Table 2). GRN levels ranged from 53 to 94 ng/ml (mean value ± SD: 68 ± 16 ng/ml) in mutation carriers, while non-GRN carriers showed levels from 115 to 386 ng/ml (mean value ± SD: 220 ± 47 ng/ml). Interestingly, GRN levels were variable among GRN mutation carriers with slightly higher expression in NGR019 (88 ng/ml) carrying the p.A9D mutation in the signal peptide sequence and NGR247 (94 ng/ml) carrying p.A472_Q548del, compared to the typical frameshift and nonsense mutation carriers (Fig. 2). Based on our data alone, any cut-off value between 94 and 115 ng/ml is associated with crude estimates of both sensitivity and specificity of 100%. By assuming normality of GRN levels after a square root transformation, we were able to explore continuous estimates of sensitivity and specificity with different cut-off values (Table 3). A cut-off value of 112 ng/ml maximized the average of the estimates of sensitivity and specificity. GRN levels in 70 control individuals ranged from 138 to 376 ng/ml (mean value ± SD: 228 ± 50 ng/ml) comparable to patients with FTLD without GRN mutations (Fig. 1). As expected, normal GRN expression (259 ng/ml) was observed in our MAPT mutation carrier.Figure 1

Bottom Line: The clinical presentation associated with GRN mutations is heterogeneous and may include clinical probable Alzheimer's disease.The approximately 75% reduction in full-length GRN, suggests an unbalanced GRN metabolism in loss-of-function mutation carriers whereby more GRN is processed into granulins.We propose that plasma GRN levels could be used as a reliable and inexpensive tool to identify all GRN mutation carriers in early-onset dementia populations and asymptomatic at-risk individuals.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.

ABSTRACT
Mutations in the progranulin gene (GRN) are an important cause of frontotemporal lobar degeneration (FTLD) with ubiquitin and TAR DNA-binding protein 43 (TDP43)-positive pathology. The clinical presentation associated with GRN mutations is heterogeneous and may include clinical probable Alzheimer's disease. All GRN mutations identified thus far cause disease through a uniform disease mechanism, i.e. the loss of functional GRN or haploinsufficiency. To determine if expression of GRN in plasma could predict GRN mutation status and could be used as a biological marker, we optimized a GRN ELISA and studied plasma samples of a consecutive clinical FTLD series of 219 patients, 70 control individuals, 72 early-onset probable Alzheimer's disease patients and nine symptomatic and 18 asymptomatic relatives of GRN mutation families. All FTLD patients with GRN loss-of-function mutations showed significantly reduced levels of GRN in plasma to about one third of the levels observed in non-GRN carriers and control individuals (P < 0.001). No overlap in distributions of GRN levels was observed between the eight GRN loss-of-function mutation carriers (range: 53-94 ng/ml) and 191 non-GRN mutation carriers (range: 115-386 ng/ml). Similar low levels of GRN were identified in asymptomatic GRN mutation carriers. Importantly, ELISA analyses also identified one probable Alzheimer's disease patient (1.4%) carrying a loss-of-function mutation in GRN. Biochemical analyses further showed that the GRN ELISA only detects full-length GRN, no intermediate granulin fragments. This study demonstrates that using a GRN ELISA in plasma, pathogenic GRN mutations can be accurately detected in symptomatic and asymptomatic carriers. The approximately 75% reduction in full-length GRN, suggests an unbalanced GRN metabolism in loss-of-function mutation carriers whereby more GRN is processed into granulins. We propose that plasma GRN levels could be used as a reliable and inexpensive tool to identify all GRN mutation carriers in early-onset dementia populations and asymptomatic at-risk individuals.

Show MeSH
Related in: MedlinePlus