A Novel Splice-Acceptor Site Mutation in GRN (c.709-2 A>T) Causes Frontotemporal Dementia Spectrum in a Large Family from Southern Italy

Celeste Sassi, Rosa Capozzo, Raphael Gibbs, Cynthia Crews, Chiara Zecca, Simona Arcuti, Massimiliano Copetti, Maria R. Barulli, Vincenzo Brescia, Andrew B. Singleton, Giancarlo Logroscino

Research output: Contribution to journalArticle

Abstract

Heterozygous loss of function mutations in granulin represent a significant cause of frontotemporal lobar degeneration with ubiquitin and TDP-43 inclusions (FTLD-TDP). We report a novel GRN splice site mutation (c.709-2 A>T), segregating with frontotemporal dementia spectrum in a large family from southern Italy. The GRN c.709-2 A>T is predicted to result in the skipping of exon 8, leading to non-sense mediated mRNA decay. Moreover, the PGRN plasma levels in the GRN c.709-2 A>T carriers were significantly lower (24ng/ml) compared to controls (142.7ng/ml) or family members non-carriers (82.0ng/ml) (p-value=0.005, Kruskal Wallis), suggesting progranulin haploinsufficiency. We do not report any potential pathogenic GRN mutation in a follow-up cohort composed of 6 FTD families and 43 sporadic FTD cases, from the same geographic area. Our study suggests that GRN (c.709-2 A>T) is a novel and likely very rare cause of FTD in this Italian cohort. Finally, in line with previous studies, we show that GRN haploinsufficiency leads to a heterogeneous clinical picture, and plasma progranulin levels may be a reliable tool to identify GRN loss of function mutations. However, given that a) genetic and environmental factors, gender, and age may regulate PGRN plasma levels and b) plasma progranulin levels may not reflect PGRN levels in the central nervous system, we suggest that the measurement of progranulin in the plasma should always be coupled with genetic screening of GRN for mutations.

Original languageEnglish
Pages (from-to)475-485
Number of pages11
JournalJournal of Alzheimer's Disease
Volume53
Issue number2
DOIs
Publication statusPublished - 2016

Keywords

  • Alzheimer's disease
  • Frontotemporal dementia
  • Progranulin
  • Splice site mutation

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Geriatrics and Gerontology
  • Clinical Psychology

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    Sassi, C., Capozzo, R., Gibbs, R., Crews, C., Zecca, C., Arcuti, S., Copetti, M., Barulli, M. R., Brescia, V., Singleton, A. B., & Logroscino, G. (2016). A Novel Splice-Acceptor Site Mutation in GRN (c.709-2 A>T) Causes Frontotemporal Dementia Spectrum in a Large Family from Southern Italy. Journal of Alzheimer's Disease, 53(2), 475-485. https://doi.org/10.3233/JAD-151170