Founder effect and estimation of the age of the Progranulin Thr272fs mutation in 14 Italian pedigrees with frontotemporal lobar degeneration.
Progranulin (PGRN) mutations have been recognized to be monogenic causes of frontotemporal lobar degeneration (FTLD). PGRN Thr272fs mutation in the Italian population has been previously identified. In the present study, we evaluated the occurrence of a founder effect studying 8 polymorphic microsatellite markers flanking the PGRN gene in 14 apparently unrelated families. We identified a common haplotype associated with PGRN Thr272fs carriers, assuming common ancestry. The inferred age analysis (range between 260 [95% credible set: 227-374] and 295 [95% credible set: 205-397] generations) places the introduction of the mutation back to the Neolithic era when the Celts, the population of that period, settled in Northern Italy. PGRN Thr272fs mutation appears to be as either behavioral frontotemporal dementia (80%) or primary progressive aphasia (20%), it was equally distributed between male and female, and the mean age at onset was 59.6 ± 5.9 (range 53-68). In 14 families, autosomal dominant pattern of inheritance was present in 64.2% of cases. No clinical predictors of disease onset were demonstrated. The identification of a large cohort of frontotemporal lobar degeneration (FTLD) patients with homogeneous genetic background well may be used in the search of disease modulators to elucidate genotype-phenotype correlations of progranulopathies.
Borroni
Barbara
B
The Centre for Ageing Brain and Neurodegenerative Disorders, Neurology Unit, University of Brescia, Brescia, Italy. bborroni@inwind.it
Bonvicini
Cristian
C
Galimberti
Daniela
D
Tremolizzo
Lucio
L
Papetti
Alice
A
Archetti
Silvana
S
Turla
Marinella
M
Alberici
Antonella
A
Agosti
Chiara
C
Premi
Enrico
E
Appollonio
Ildebrando
I
Rainero
Innocenzo
I
Ferrarese
Carlo
C
Gennarelli
Massimo
M
Scarpini
Elio
E
Padovani
Alessandro
A
D017668:Age of Onset; D000368:Aged; D001921:Brain / Q000098:blood supply / Q000473:pathology; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000379:methods; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D007558:Italy / Q000453:epidemiology; D008279:Magnetic Resonance Imaging; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D010100:Oxygen / Q000097:blood; D010375:Pedigree; D010649:Phenylalanine / Q000235:genetics*; D000077153:Progranulins; D013912:Threonine / Q000235:genetics*
C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D013912:Threonine; D010649:Phenylalanine; D010100:Oxygen