title: Progranulin peripheral levels as a screening tool for the identification of subjects with progranulin mutations in a Portuguese cohort.
abstract: BACKGROUND
  Progranulin (PGRN) mutations are associated with different clinical phenotypes, including frontotemporal lobar degeneration (FTLD), corticobasal syndrome (CBS) and Alzheimer's disease (AD). As all pathogenic PGRN mutations identified so far cause disease through haploinsufficiency, determination of PGRN levels has been proposed as a reliable method to identify mutation carriers.
  
  
  OBJECTIVE
  To evaluate the accuracy of peripheral PGRN levels in the identification of the PGRN mutation carriers detected thus far in our Portuguese cohort.
  
  
  METHODS
  Serum PGRN levels were measured in 244 subjects (124 patients in the spectrum of FTLD, 2 asymptomatic descendants of a FTLD patient, 56 AD patients and 64 controls) by a novel commercial ELISA kit.
  
  
  RESULTS
  Low PGRN levels were detected in 7 individuals (5 behavioral variant frontotemporal dementia, 1 CBS, and 1 still clinically unaffected) that constituted the group of the null PGRN mutation carriers previously identified in our molecular diagnostic laboratory. The pathogenic mutations found consisted of 4 insertion-deletions, causing frameshifts resulting in premature stop codons, 3 of which were novel. In addition, a normal PGRN level was found in a patient harboring a novel missense variant. For this novel ELISA kit, we established a PGRN cut-off level that identified with 100% accuracy the pathogenic mutation carriers.
  
  
  CONCLUSIONS
  This study supports the use of a novel assay for the determination of PGRN levels as a screening procedure to identify patients harboring null PGRN mutations. This approach would significantly decrease the required PGRN mutation analysis workload and should be extended to other clinical phenotypes than behavioral variant frontotemporal dementia and to apparently sporadic cases.
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: Maria Rosário
authors.initials: MR
authors.lastname: Almeida
authors.forename: Inês
authors.initials: I
authors.lastname: Baldeiras
authors.forename: Maria Helena
authors.initials: MH
authors.lastname: Ribeiro
authors.forename: Beatriz
authors.initials: B
authors.lastname: Santiago
authors.forename: Cristina
authors.initials: C
authors.lastname: Machado
authors.forename: João
authors.initials: J
authors.lastname: Massano
authors.forename: Joana
authors.initials: J
authors.lastname: Guimarães
authors.forename: Catarina
authors.initials: C
authors.lastname: Resende Oliveira
authors.forename: Isabel
authors.initials: I
authors.lastname: Santana
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000097:blood / Q000175:diagnosis* / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D057180:Frontotemporal Dementia / Q000097:blood / Q000175:diagnosis* / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011174:Portugal / Q000453:epidemiology; D000077153:Progranulins
chemical_list: C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins