Author/Authors :
Adolfo L?pez de Munain، نويسنده , , Ainhoa Alzualde، نويسنده , , Ana Gorostidi، نويسنده , , David Otaegui، نويسنده , , Javier Ruiz-Mart?nez، نويسنده , , Bego?a Indakoetxea، نويسنده , , Isidro Ferrer، نويسنده , , Jordi Pérez-Tur، نويسنده , , Amets S?enz، نويسنده , , Alberto Bergareche، نويسنده , , Miriam Barandiar?n، نويسنده , , Juan José Poza، نويسنده , , Ram?n Zabalza، نويسنده , , Irune Ruiz، نويسنده , , Miguel Urtasun، نويسنده , , I?aki Fern?ndez-Manchola، نويسنده , , Bixen Olasagasti، نويسنده , , Juan Bautista Espinal، نويسنده , , Javier Olaskoaga، نويسنده , , Marta Ruibal، نويسنده , , et al.، نويسنده ,
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 τ/α-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.