TY - JOUR
T1 - A Novel Splice-Acceptor Site Mutation in GRN (c.709-2 A>T) Causes Frontotemporal Dementia Spectrum in a Large Family from Southern Italy
AU - Sassi, Celeste
AU - Capozzo, Rosa
AU - Gibbs, Raphael
AU - Crews, Cynthia
AU - Zecca, Chiara
AU - Arcuti, Simona
AU - Copetti, Massimiliano
AU - Barulli, Maria R.
AU - Brescia, Vincenzo
AU - Singleton, Andrew B.
AU - Logroscino, Giancarlo
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - Frontotemporal dementia
KW - Progranulin
KW - Splice site mutation
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U2 - 10.3233/JAD-151170
DO - 10.3233/JAD-151170
M3 - Article
AN - SCOPUS:84979299414
VL - 53
SP - 475
EP - 485
JO - Journal of Alzheimer's Disease
JF - Journal of Alzheimer's Disease
SN - 1387-2877
IS - 2
ER -