A Novel Splice-Acceptor Site Mutation in GRN (c.709-2 A>T) Causes Frontotemporal Dementia Spectrum in a Large Family from Southern Italy.
J Alzheimers Dis
; 53(2): 475-85, 2016 05 30.
Article
en En
| MEDLINE
| ID: mdl-27258413
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 (24âng/ml) compared to controls (142.7âng/ml) or family members non-carriers (82.0âng/ml) (p-valueâ=â0.005, 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.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Salud de la Familia
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Sitios de Empalme de ARN
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Péptidos y Proteínas de Señalización Intercelular
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Demencia Frontotemporal
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Mutación
Tipo de estudio:
Etiology_studies
/
Incidence_studies
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Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Límite:
Adult
/
Aged
/
Aged80
/
Female
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Humans
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Male
/
Middle aged
País/Región como asunto:
Europa
Idioma:
En
Revista:
J Alzheimers Dis
Asunto de la revista:
GERIATRIA
/
NEUROLOGIA
Año:
2016
Tipo del documento:
Article
País de afiliación:
Estados Unidos