title: Progranulin mutation causes frontotemporal dementia in the Swedish Karolinska family.
abstract: BACKGROUND
  Frontotemporal dementia (FTD) is a neurodegenerative disease characterized by cognitive impairment, language dysfunction, and/or changes in personality. Recently it has been shown that progranulin (GRN) mutations can cause FTD as well as other neurodegenerative phenotypes.
  
  
  METHODS
  DNA from 30 family members, of whom seven were diagnosed with FTD, in the Karolinska family was available for GRN sequencing. Fibroblast cell mRNA from one affected family member and six control individuals was available for relative quantitative real-time polymerase chain reaction to investigate the effect of the mutation. Furthermore, the cDNA of an affected individual was sequenced.
  
  
  RESULTS
  Clinical and neuropathologic findings of a previously undescribed family branch are presented. A frameshift mutation in GRN (g.102delC) was detected in all affected family members and absent in four unaffected family members older than 70 years. Real-time polymerase chain reaction data showed an approximately 50% reduction of GRN fibroblast mRNA in an affected individual. The mutated mRNA transcripts were undetectable by cDNA sequencing.
  
  
  CONCLUSIONS
  Segregation and RNA analyses showed that the g.102delC mutation, previously reported, causes FTD in the Karolinska family. Our findings add further support to the significance of GRN in FTD etiology and the presence of modifying genes, which emphasize the need for further studies into the mechanisms of clinical heterogeneity. However, the results already call for attention to the complexity of predictive genetic testing of GRN mutations.
authors.affiliation: Karolinska Institutet, Department NVS, KI-Alzheimer Disease Research Center, Novum, Huddinge, Stockholm, Sweden.
authors.forename: Huei-Hsin
authors.initials: HH
authors.lastname: Chiang
authors.forename: Lina
authors.initials: L
authors.lastname: Rosvall
authors.forename: Jesper
authors.initials: J
authors.lastname: Brohede
authors.forename: Karin
authors.initials: K
authors.lastname: Axelman
authors.forename: Behnosh F
authors.initials: BF
authors.lastname: Björk
authors.forename: Inger
authors.initials: I
authors.lastname: Nennesmo
authors.forename: Tiina
authors.initials: T
authors.lastname: Robins
authors.forename: Caroline
authors.initials: C
authors.lastname: Graff
mesh_terms: D017668:Age of Onset; D000368:Aged; D003072:Cognition Disorders / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D004252:DNA Mutational Analysis; D003704:Dementia / Q000235:genetics* / Q000473:pathology / Q000523:psychology; D016368:Frameshift Mutation; D005625:Frontal Lobe; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D009483:Neuropsychological Tests; D010375:Pedigree; D010641:Phenotype; D000077153:Progranulins; D013548:Sweden; D013702:Temporal Lobe; D044465:White People / Q000235:genetics*
chemical_list: C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins