Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C→T (Arg493X) mutation: an international initiative

Granulin mutations associated with frontotemporal lobar degeneration and related disorders: An update

“…In two of these studies Beck et al, 2008], significant association of the APOE genotype with onset age was found; however, these findings were not replicated Bruni et al, 2007;Rademakers et al, 2007]. Also no influence of the two major MAPT haplotypes H1 and H2 could be detected Gass et al, 2006;Bruni et al, 2007;Rademakers et al, 2007]. In addition, it might still be important to investigate whether different degrees of NMD efficiency [Linde et al, 2007] might lead to the variability in phenotypic features.…”

“…The loss of functional protein is mainly the result of loss of GRN transcript caused by NMD of transcripts containing PTCs (n 5 52) or by nuclear degradation of transcripts retaining the first intron due to splice-site mutations in intron 1 (n 5 2) Le Ber et al, 2007]. PTCs can be the result from nonsense mutations (n 5 12), splice-site mutations (n 5 10), and small insertions/deletions (n 5 30) Baker et al, 2006;Huey et al, 2006;Pickering-Brown et al, 2006Boeve et al, 2006;Masellis et al, 2006;Gass et al, 2006;Benussi et al, 2008;Bronner et al, 2007;Mesulam et al, 2007;Behrens et al, 2007;Leverenz et al, 2007;Bruni et al, 2007;Van Deerlin et al, 2007;Brouwers et al, 2007;Rademakers et al, 2007;Llado et al, 2007;Le Ber et al, 2007;Davion et al, 2007;Kelley et al, in press;Spina et al, 2007a;Mukherjee et al, 2008;Beck et al, 2008;Le Ber et al, 2008]. Second, loss of translation as a result of mutations affecting the Kozak sequence (n 5 4) Baker et al, 2006;Pickering-Brown et al, 2006;Boeve et al, 2006;Gass et al, 2006;Le Ber et al, 2008] and reduction of secreted protein due to missense mutations affecting the signal sequence (n 5 2) [Mukherjee et al, 2006;Gass et al, 2006;Kelley et al, in press;Mukherjee et al, 2008;Le Ber et al, 2008], results in reduced GRN.…”

“…In addition, mild parkinsonian features are frequent but motor neuron disease was remarkably rare Josephs et al, 2007;Mackenzie, 2007]. Furthermore, other neurodegenerative brain diseases including corticobasal syndrome (CBS) [Masellis et al, 2006;Benussi et al, 2008;Rademakers et al, 2007;Le Ber et al, 2007;Lopez de Munain et al, 2008;Spina et al, 2007b;Le Ber et al, 2008], AD [van Duijn et al, 1994;Rademakers et al, 2002;Brouwers et al, 2007;Rademakers et al, 2007] and PD [Brouwers et al, 2007] were also linked with GRN mutations. However, compared to variants with unclear pathogenic significance, GRN null mutations were not frequently found in patients with a disease other than FTLD Schymick et al, 2007;Brouwers et al, 2007;Sleegers et al, in press;Pickering-Brown et al, 2008].…”

“…However, replications are needed and the functional variant remains to be elucidated. The influence of the apolipoprotein E (APOE) genotype on the clinical expression has already been studied Gass et al, 2006;Bruni et al, 2007;Rademakers et al, 2007;Beck et al, 2008]. In two of these studies Beck et al, 2008], significant association of the APOE genotype with onset age was found; however, these findings were not replicated Bruni et al, 2007;Rademakers et al, 2007].…”

“…The influence of the apolipoprotein E (APOE) genotype on the clinical expression has already been studied Gass et al, 2006;Bruni et al, 2007;Rademakers et al, 2007;Beck et al, 2008]. In two of these studies Beck et al, 2008], significant association of the APOE genotype with onset age was found; however, these findings were not replicated Bruni et al, 2007;Rademakers et al, 2007]. Also no influence of the two major MAPT haplotypes H1 and H2 could be detected Gass et al, 2006;Bruni et al, 2007;Rademakers et al, 2007].…”