title: Progranulin mutations in primary progressive aphasia: the PPA1 and PPA3 families.
abstract: BACKGROUND
  Primary progressive aphasia (PPA) is a language-based dementia characterized by fluent or nonfluent language disorder as its principal feature.
  
  
  OBJECTIVE
  To describe progranulin gene mutations in 2 families with PPA.
  
  
  METHODS
  Report of affected families.
  
  
  METHODS
  Academic research.
  
  
  METHODS
  Two families, PPA1 and PPA3, were studied. Genomic DNA was isolated from 3 of 4 siblings in PPA1, from all 3 siblings in PPA3, and from more than 200 control subjects.
  
  
  METHODS
  All 12 coding exons of the progranulin gene and the 5" and 3" untranslated regions were amplified by polymerase chain reaction and were sequenced in both directions using relevant primers.
  
  
  RESULTS
  Both affected members of PPA1 for whom DNA was available and both affected sisters of PPA3 had a progranulin gene mutation not found in the unaffected siblings or in the controls. The mutations likely cause a null allele and a reduction in the level of functional progranulin protein. Both affected members of PPA1 with autopsies had frontotemporal lobar degeneration with tau-negative ubiquinated inclusions.
  
  
  CONCLUSIONS
  To our knowledge, these are the only known families in which affected members display phenotypical homogeneity for PPA in the initial stages of the disease. In both families, the disease segregated with progranulin gene mutations. Whether progranulin dysfunction also extends to sporadic PPA and how it affects the initial anatomical specificity of neurodegeneration remain to be determined.
authors.affiliation: Cognitive Neurology and Alzheimer's Disease Center and Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Ill 60611, USA. mmesulam@northwestern.edu
authors.forename: Marsel
authors.initials: M
authors.lastname: Mesulam
authors.forename: Nancy
authors.initials: N
authors.lastname: Johnson
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Krefft
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Gass
authors.forename: Ashley D
authors.initials: AD
authors.lastname: Cannon
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Adamson
authors.forename: Eileen H
authors.initials: EH
authors.lastname: Bigio
authors.forename: Sandra
authors.initials: S
authors.lastname: Weintraub
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.forename: Michael L
authors.initials: ML
authors.lastname: Hutton
authors.forename: Neill R
authors.initials: NR
authors.lastname: Graff-Radford
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D018888:Aphasia, Primary Progressive / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis / Q000379:methods; D005192:Family Health; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D036341:Intercellular Signaling Peptides and Proteins / Q000145:classification / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D000077153:Progranulins; D025801:Ubiquitin / Q000378:metabolism
chemical_list: C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D025801:Ubiquitin