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P3‐279: A novel progranulin mutation in a large frontotemporal dementia calabrian kindred

2008; Wiley; Volume: 4; Issue: 4S_Part_18 Linguagem: Inglês

10.1016/j.jalz.2008.05.1847

1552-5279

Francesca Frangipane, Rosanna Colao, Maria Mirabelli, Gianfranco Puccio, Livia Bernardi, Carmine Tomaino, Maria Anfossi, Maura Gallo, Silvana Geracitano, Raffaele Maletta, Nicoletta Smirne, Joshua W. Elder, Toshitaka Kawarai, Christine Sato, Silvia Pradella, Yosuke Wakutani, Andrew Kertesz, Peter St George‐Hyslop, John Hardy, Ekaterina Rogaeva, Parastoo Momeni, Amalia C. Bruni,

Cerebrovascular and genetic disorders

Frontotemporal dementia (FTD) in several 17q21-linked families was recently explained by truncating mutations in the progranulin gene (GRN). Objective of this study is to determine the frequency of GRN mutations in a cohort of Caucasian FTD patients without mutations in known FTD genes. GRN was sequenced in a series of 78 independent FTD patients including 23 familial subjects. A different Calabrian dataset (109 normal controls and 96 FTD patients) was used to establish the frequency of the GRN mutation A novel truncating GRN mutation (c.1145insA) was detected in a proband of an extended consanguineous Calabrian kindred. Segregation analysis of 70 family members revealed 19 heterozygous mutation carriers including 9 patients affected by FTD. The absence of homozygous carriers in highly consanguineous kindred may indicate that the loss of both GRN alleles might lead to embryonic lethality. An extremely variable age-at-onset in the mutation carriers (more than five decades apart) is not explained by APOE genotypes or the H1/H2 MAPT haplotypes. Intriguingly, the mutation was excluded in four FTD patients belonging to branches with an autosomal dominant mode of inheritance of FTD, suggesting that another novel FTD gene accounts for the disease in the phenocopies. It is difficult to clinically distinguish phenocopies from GRN mutation carriers, except that language in mutation carriers was more severely compromised. The current results imply further genetic heterogeneity of FTD, since we detected only one GRN-linked family (∼1%). The value of discovering large kindred includes the possibility of a longitudinal study of GRN mutation carriers.