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This Article Figures Only Full Text Full Text (PDF) CME: Take the course for this article: Volume 69, Number 02, July 10, 2007 Correspondence: Submit a response Alert me when this article is cited Alert me when Correspondence are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bruni, A. C. Articles by Rogaeva, E. Search for Related Content PubMed PubMed Citation Articles by Bruni, A. C. Articles by Rogaeva, E. Related Collections Frontotemporal dementia Dementia aphasia Cognitive neuropsychology in dementia All Genetics Related Article

Heterogeneity within a large kindred with frontotemporal dementia

A novel progranulin mutation

From the Regional Neurogenetic Centre (A.C.B., L.B., C.T., F.F., M.A., M.G., S.G., A.C., N.S., S.A.M.C., M.M., G.P., R.C., R.G.M.), Lamezia Terme; Department of Neurology and Psychiatry (S.P.), University of Florence, Firenze, Italy; Department of Neurology (P.M.), Texas Tech University Health Sciences Center, Lubbock; Laboratory of Neurogenetics (J.E., J.H.), National Institute on Aging, Bethesda, MD; Centre for Research in Neurodegenerative Diseases (T.K., C.S., Y.W., P.S.G.-H., E.R.), Department of Medicine, University of Toronto, Toronto Western Hospital Research Institute (P.S.G.-H.), University Health Network, Department of Medicine (P.S.G.-H., E.R.), Division of Neurology, University of Toronto, and Department of Clinical Neurological Sciences (A.K.), St. Joseph's Health Centre, University of Western Ontario, London, Canada.

Address correspondence and reprint requests to Dr Bruni, Centro Regionale di Neurogenetica AS6, Viale A. Perugini 88046 Lamezia Terme, CZ, Italy bruni{at}arn.it

Background: Frontotemporal dementia (FTD) in several 17q21-linked families was recently explained by truncating mutations in the progranulin gene (GRN).

Objective: To determine the frequency of GRN mutations in a cohort of Caucasian patients with FTD without mutations in known FTD genes.

Methods: GRN was sequenced in a series of 78 independent FTD patients including 23 familial subjects. A different Calabrian dataset (109 normal control subjects and 96 FTD patients) was used to establish the frequency of the GRN mutation.

Results: 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 a 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.

Conclusion: The current results imply further genetic heterogeneity of frontotemporal dementia, as we detected only one GRN-linked family (about 1%). The value of discovering large kindred includes the possibility of a longitudinal study of GRN mutation carriers.

Editorial, see page 129

*These authors contributed equally to the work as co-first authors.

Supported by grants from the Canadian Institutes of Health Research, Howard Hughes Medical Institute, Canada Foundation for Innovation (P.H.), Japan-Canada and Canadian Institutes of Health Research Joint Health Research Program, Parkinson Society of Canada, W. Garfield Weston Fellows (E.R.), fellowship from the Japanese Society for the Promotion of Science, Japan (T.K.), and NIA/NIH Intramural Program (J.H.). A.C.B. and the team at the Regional Neurogenetic Centre were supported in part by grants from the Italian Ministry of Health (finalized projects no. 2002/156; no. 2003/42) and the Calabria Regional Health Department.

Disclosure: The authors report no conflicts of interest.

Received December 7, 2007. Accepted in final form February 28, 2007.

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