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Progranulin genetic variations in frontotemporal lobar degeneration: evidence for low mutation frequency in an Italian clinical series

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Abstract

Frontotemporal lobar degeneration (FTLD) recognises high familial incidence, with up to 50% of patients reported to have a family history of similar dementia. It has been reported that mutations within progranulin (PGRN) gene are a major cause of FTLD in the USA and worldwide, counting for 5–10% of FTLD and for 20–25% of familiar FTLD cases. The aim of the present study was to define the role of PGRN genetic variations in a large sample of consecutive patients with FTLD in Italy. Two-hundred forty-three FTLD patients were investigated. Each subject performed a clinical and neuropsychological evaluation, a functional and structural brain imaging, and the diagnosis was confirmed by at least 1 year follow-up. PGRN sequencing was performed in all FTLD patients and in 121 healthy age-matched controls drawn from the same geographic area. Only one PGRN pathogenetic mutation was found, consisting of a four-base pair deletion in the coding sequence of exon 8 (delCACT). This mutation was recognised in four patients, being the overall frequency of mutations in our clinical series of 1.64%. Considering only patients with a well-known family history for dementia, the frequency of this mutation was 6%. Moreover, four missense mutations within intron regions (g.100474G>A, g.100674G>A, g.101266G>A, g.102070G>A) were found. The frequency of these genetic variations did not differ in patients compared to controls, and they did not influence on clinical FTLD phenotype. In conclusion, this study supports a lower frequency of PGRN mutations amongst FTLD patients in Italy compared to literature data and further underlies the genetic heterogeneity of FTLD.

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Abbreviations

bvFTD:

behavioural variant frontotemporal dementia

CBDS:

corticobasal degeneration syndrome

FTLD:

frontotemporal lobar degeneration

SD:

semantic dementia

MAPT:

microtubule-associated protein tau

PGRN:

progranulin

PNFA:

progressive non-fluent aphasia

PSP:

progressive supranuclear palsy

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Acknowledgement

The authors are grateful to Dr. Enrico Premi for the clinical assessment and to Mrs. Maria Gervasi for her valuable technical support. The authors are in debt to Dr Francesca Piazza for linguistic editing of the manuscript.

This work was supported by Centre for Behavioural Disturbances and Neurodegenerative Diseases EULO (Ente Universitario Lombardia Orientale) to P.A.

Author information

Authors and Affiliations

  1. Department of Neurology, University of Brescia, Brescia, Italy

    Barbara Borroni, Antonella Alberici, Chiara Agosti, Barbara Bigni & Alessandro Padovani

  2. Laboratory of Biotechnology, Department of Diagnostic of Laboratories, University of Brescia, Brescia, Italy

    Silvana Archetti, Maria Ferrari, Diego Di Lorenzo & Luigi Caimi

  3. Genetic Unit, IRCCS Brescia, Brescia, Italy

    Massimo Gennarelli & Cristian Bonvicini

  4. Rehabilitation and Geriatric Unit, “Ancelle della Carità” Hospital, Cremona, Italy

    Giuseppe Bellelli

  5. Department of Neurology, University of Milan, Milan, Italy

    Daniela Galimberti & Elio Scarpini

  6. Department of Neurology and IRCCS Fondazione S. Lucia, “Tor Vergata” University, Rome, Italy

    Carlo Caltagirone

  7. Department of Pharmacological Sciences, University of Milan, Milan, Italy

    Monica Di Luca

  8. Clinica Neurologica, Università degli Studi di Brescia, Pza Spedali Civili, 1-25100, Brescia, Italy

    Barbara Borroni

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  1. Barbara Borroni
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Correspondence to Barbara Borroni.

Appendices

Appendix 1. Primers used for the analysis of progranulin sequence

Table 5
Full size table

F: forward primer; R: reverse primer; M: middle F/R

Appendix 2. Primers used for microsatellite haplotyping and methods

Table 6
Full size table

F: forward primer; R: reverse primer

Microsatellite haplotype and analysis

Polymerase chain reaction (PCR) amplicons were generated using fluorescently end-labelled primers reported in the table above at 500 mM for microsatellite markers D17S1818(HEX) [GenBank Accession: Z52895], D17S1814(TAMRA) [GenBank Accession: Z52854], D17S1787(FAM) [GenBank Accession: Z52130], D17S1793(HEX) [GenBank Accession: Z52280], D17S951(FAM) [GenBank Accession: Z24197], D17S1861(FAM) [GenBank Accession: Z53921] and D17S934(HEX) [GenBank Accession: Z23831]. A loading mix of 1 μl amplicon, 9.75 μl HiDi formamide (ABI) and 0.25 μl 400HD size standard (ABI) was prepared, and DNA products were electrophoresed on an ABI 3130xl automated sequencer. Data were analysed using ABI GeneMapper software v4.0.

The haplotype frequency estimation calculated from the observed genotypes were tested using Arlequin 2000 and Phase 2.1 softwares

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Borroni, B., Archetti, S., Alberici, A. et al. Progranulin genetic variations in frontotemporal lobar degeneration: evidence for low mutation frequency in an Italian clinical series. Neurogenetics 9, 197–205 (2008). https://doi.org/10.1007/s10048-008-0127-3

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