title: Heterogeneity within a large kindred with frontotemporal dementia: a novel progranulin mutation.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Regional Neurogenetic Centre, Lamezia Terme, CZ, Italy. bruni@arn.it
authors.forename: A C
authors.initials: AC
authors.lastname: Bruni
authors.forename: P
authors.initials: P
authors.lastname: Momeni
authors.forename: L
authors.initials: L
authors.lastname: Bernardi
authors.forename: C
authors.initials: C
authors.lastname: Tomaino
authors.forename: F
authors.initials: F
authors.lastname: Frangipane
authors.forename: J
authors.initials: J
authors.lastname: Elder
authors.forename: T
authors.initials: T
authors.lastname: Kawarai
authors.forename: C
authors.initials: C
authors.lastname: Sato
authors.forename: S
authors.initials: S
authors.lastname: Pradella
authors.forename: Y
authors.initials: Y
authors.lastname: Wakutani
authors.forename: M
authors.initials: M
authors.lastname: Anfossi
authors.forename: M
authors.initials: M
authors.lastname: Gallo
authors.forename: S
authors.initials: S
authors.lastname: Geracitano
authors.forename: A
authors.initials: A
authors.lastname: Costanzo
authors.forename: N
authors.initials: N
authors.lastname: Smirne
authors.forename: S A M
authors.initials: SA
authors.lastname: Curcio
authors.forename: M
authors.initials: M
authors.lastname: Mirabelli
authors.forename: G
authors.initials: G
authors.lastname: Puccio
authors.forename: R
authors.initials: R
authors.lastname: Colao
authors.forename: R G
authors.initials: RG
authors.lastname: Maletta
authors.forename: A
authors.initials: A
authors.lastname: Kertesz
authors.forename: P
authors.initials: P
authors.lastname: St George-Hyslop
authors.forename: J
authors.initials: J
authors.lastname: Hardy
authors.forename: E
authors.initials: E
authors.lastname: Rogaeva
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D003704:Dementia / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D006580:Genetic Carrier Screening / Q000379:methods; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D007558:Italy / Q000208:ethnology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D000077153:Progranulins
chemical_list: C492314:GRN protein, human; D005819:Genetic Markers; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins