RGD Reference Report - Plasma progranulin levels predict progranulin mutation status in frontotemporal dementia patients and asymptomatic family members. - Rat Genome Database

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

Authors: 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 
Citation: Finch N, etal., Brain. 2009 Mar;132(Pt 3):583-91. doi: 10.1093/brain/awn352. Epub 2009 Jan 21.
RGD ID: 10401634
Pubmed: PMID:19158106   (View Abstract at PubMed)
PMCID: PMC2664450   (View Article at PubMed Central)
DOI: DOI:10.1093/brain/awn352   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Frontotemporal Lobar Degeneration  IAGP 10401634DNA more ...RGD 
Frontotemporal Lobar Degeneration  ISOGRN (Homo sapiens)10401634; 10401634DNA more ...RGD 

Objects Annotated

Genes (Rattus norvegicus)
Grn  (granulin precursor)

Genes (Mus musculus)
Grn  (granulin)

Genes (Homo sapiens)
GRN  (granulin precursor)


Additional Information