RGD Reference Report - Progranulin genetic variability contributes to amyotrophic lateral sclerosis. - Rat Genome Database

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Progranulin genetic variability contributes to amyotrophic lateral sclerosis.

Authors: Sleegers, K  Brouwers, N  Maurer-Stroh, S  Van Es, MA  Van Damme, P  Van Vught, PW  Van der Zee, J  Serneels, S  De Pooter, T  Van den Broeck, M  Cruts, M  Schymkowitz, J  De Jonghe, P  Rousseau, F  Van den Berg, LH  Robberecht, W  Van Broeckhoven, C 
Citation: Sleegers K, etal., Neurology. 2008 Jul 22;71(4):253-9. Epub 2008 Jan 9.
RGD ID: 5509619
Pubmed: PMID:18184915   (View Abstract at PubMed)
DOI: DOI:10.1212/01.wnl.0000289191.54852.75   (Journal Full-text)

OBJECTIVES: Null mutations in progranulin (PGRN) cause ubiquitin-positive frontotemporal dementia (FTD) linked to chromosome 17q21 (FTDU-17). Here we examined PGRN genetic variability in amyotrophic lateral sclerosis (ALS), a neurodegenerative motor neuron disease that overlaps with FTD at a clinical, pathologic, and epidemiologic level. METHODS: We sequenced all exons, exon-intron boundaries, and 5' and 3' regulatory regions of PGRN in a Belgian sample of 230 patients with ALS. The frequency of observed genetic variants was determined in 436 healthy control individuals. The contribution of eight frequent polymorphisms to ALS risk, onset age, and survival was assessed in an association study in the Belgian sample and a replication series of 308 Dutch patients with ALS and 345 Dutch controls. RESULTS: In patients with ALS we identified 11 mutations, 5 of which were predicted to affect PGRN protein sequence or levels (four missense mutations and one 5' regulatory variant). Moreover, common variants (rs9897526, rs34424835, and rs850713) and haplotypes were significantly associated with a reduction in age at onset and a shorter survival after onset of ALS in both the Belgian and the Dutch studies. CONCLUSION: PGRN acts as a modifier of the course of disease in patients with amyotrophic lateral sclerosis, through earlier onset and shorter survival.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
amyotrophic lateral sclerosis onsetIAGP 5509619DNA:mutations: :RGD 
amyotrophic lateral sclerosis onsetISOGRN (Homo sapiens)5509619; 5509619DNA:mutations: :RGD 

Objects Annotated

Genes (Rattus norvegicus)
Grn  (granulin precursor)

Genes (Mus musculus)
Grn  (granulin)

Genes (Homo sapiens)
GRN  (granulin precursor)


Additional Information