Founder effect and estimation of the age of the Progranulin Thr272fs mutation in 14 Italian pedigrees with frontotemporal lobar degeneration

The Centre for Ageing Brain and Neurodegenerative Disorders, Neurology Unit, University of Brescia, Brescia, Italy.
Neurobiology of aging (Impact Factor: 5.01). 10/2010; 32(3):555.e1-8. DOI: 10.1016/j.neurobiolaging.2010.08.009
Source: PubMed


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.

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Available from: Cristian Bonvicini, Mar 14, 2014
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    • "A venous blood sample was drawn from each patient for TREM2 exon 2 sequencing. Patients with MAPT or GRN mutations and with repeat expansion of C9orf72 gene were excluded (Borroni et al., 2011; Galimberti et al., 2013). Moreover, a control group similar in age and gender composition was recruited in the same Italian area from which the patients were drawn and was sequenced for TREM2 exon 2 genetic variations. "
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