Mutations in progranulin gene: clinical, pathological, and ribonucleic acid expression findings.
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.
López de Munain
Adolfo
A
Servicio de Neurología, Hospital Donostia, San Sebastián, Spain. munain@chdo.osakidetza.net
Alzualde
Ainhoa
A
Gorostidi
Ana
A
Otaegui
David
D
Ruiz-Martínez
Javier
J
Indakoetxea
Begoña
B
Ferrer
Isidro
I
Pérez-Tur
Jordi
J
Sáenz
Amets
A
Bergareche
Alberto
A
Barandiarán
Miriam
M
Poza
Juan José
JJ
Zabalza
Ramón
R
Ruiz
Irune
I
Urtasun
Miguel
M
Fernández-Manchola
Iñaki
I
Olasagasti
Bixen
B
Espinal
Juan Bautista
JB
Olaskoaga
Javier
J
Ruibal
Marta
M
Moreno
Fermin
F
Carrera
Nieves
N
Martí Massó
José Félix
JF
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
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