title: Mutations in progranulin gene: clinical, pathological, and ribonucleic acid expression findings.
abstract: BACKGROUND
  There is an increasing interest in the clinico-pathological correlation of mutations in progranulin (PGRN) and frontotemporal lobar degeneration (FTLD) complex diseases. We aim to study the PGRN expression variability in patients with different clinical features for a better understanding of its roles in FTLD disease.
  
  
  METHODS
  We sequenced the PGRN gene in 72 patients suffering from FTLD (25 familial and 47 sporadic cases) and in 24 asymptomatic at-risk relatives. We also analyzed PGRN expression in blood by quantitative real-time polymerase chain reaction from 37 patients, 8 asymptomatic mutation carriers, and 10 control subjects as well as in brain tissue from 16 patients and 9 control subjects.
  
  
  RESULTS
  Four novel mutations were associated with familial and sporadic FTLD and familial dementia associated with amyotrophic lateral sclerosis. We identified a close association between the IVS6-1G>A mutation in PGRN and corticobasal syndrome. Brain tissue was available for carriers of two of the four mutations (IVS6-1 G>A and P357HfsX3). Immunohistochemical analysis revealed ubiquitin- and TDP-43positive and tau/alpha-synuclein negative immunoreactive neuronal intranuclear inclusions. The relative expression of PGRN in the clinical sample was significantly lower in carriers of the IVS6-1 G>A than in control subjects.
  
  
  CONCLUSIONS
  Progranulopathies are a major cause of the main phenotypes included in the FTLD complex. According to our results, the level of expression of PGRN in blood could be a useful marker both for diagnostics of part of the spectrum of FTLD conditions and for monitoring future treatments that might boost the level of PGRN in this disorder.
authors.affiliation: Servicio de Neurología, Hospital Donostia, San Sebastián, Spain. munain@chdo.osakidetza.net
authors.forename: Adolfo
authors.initials: A
authors.lastname: López de Munain
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Alzualde
authors.forename: Ana
authors.initials: A
authors.lastname: Gorostidi
authors.forename: David
authors.initials: D
authors.lastname: Otaegui
authors.forename: Javier
authors.initials: J
authors.lastname: Ruiz-Martínez
authors.forename: Begoña
authors.initials: B
authors.lastname: Indakoetxea
authors.forename: Isidro
authors.initials: I
authors.lastname: Ferrer
authors.forename: Jordi
authors.initials: J
authors.lastname: Pérez-Tur
authors.forename: Amets
authors.initials: A
authors.lastname: Sáenz
authors.forename: Alberto
authors.initials: A
authors.lastname: Bergareche
authors.forename: Miriam
authors.initials: M
authors.lastname: Barandiarán
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Poza
authors.forename: Ramón
authors.initials: R
authors.lastname: Zabalza
authors.forename: Irune
authors.initials: I
authors.lastname: Ruiz
authors.forename: Miguel
authors.initials: M
authors.lastname: Urtasun
authors.forename: Iñaki
authors.initials: I
authors.lastname: Fernández-Manchola
authors.forename: Bixen
authors.initials: B
authors.lastname: Olasagasti
authors.forename: Juan Bautista
authors.initials: JB
authors.lastname: Espinal
authors.forename: Javier
authors.initials: J
authors.lastname: Olaskoaga
authors.forename: Marta
authors.initials: M
authors.lastname: Ruibal
authors.forename: Fermin
authors.initials: F
authors.lastname: Moreno
authors.forename: Nieves
authors.initials: N
authors.lastname: Carrera
authors.forename: José Félix
authors.initials: JF
authors.lastname: Martí Massó
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000378:metabolism; D003704:Dementia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015870:Gene Expression / Q000502:physiology*; D020022:Genetic Predisposition to Disease; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D045586:Intranuclear Inclusion Bodies / Q000473:pathology; D008297:Male; D009154:Mutation / Q000235:genetics*; D009483:Neuropsychological Tests; D000077153:Progranulins; D012313:RNA / Q000378:metabolism*; D012189:Retrospective Studies; D017421:Sequence Analysis; D025801:Ubiquitin / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C054369:MAPT protein, human; D000077153:Progranulins; D025801:Ubiquitin; D051844:alpha-Synuclein; D016875:tau Proteins; D012313:RNA