Mutations other than null mutations producing a pathogenic loss of progranulin in frontotemporal dementia

Abstract

Null mutations in the progranulin gene (GRN, PGRN) were recently identified as the causal mechanism underlying frontotemporal dementia (FTD) with ubiquitin-positive brain pathology linked to chromosome 17 (FTDU-17). In a Belgian and French FTD series comprising 332 patients, we reported 13 PGRN null mutations which were mainly nonsense and frameshift mutations resulting in premature stop codons. Here we report in the same patient series three missense mutations of which two (c.743C>T, p.Pro248Leu and c.1294C>T, p.Arg432Cys) were predicted in silico to severely affect protein folding and/or processing leading to PGRN protein haploinsufficiency. In addition, we observed three sequence variations in the 5' regulatory region that might potentially affect PGRN transcription activity. Our findings extend the mutation spectrum in PGRN leading to loss of functional PGRN as the basis for FTD.

Novel progranulin mutations with reduced serum-progranulin levels in frontotemporal lobar degeneration

“…Of the three unaffected carriers, one was above the mean age at onset and the other two were under the age at onset, showing a variable age at onset which is in agreement with previous reports (Supplementary Figure 1). 7,18,[23][24][25] One splice site variation c.462 þ 1G4C (numbering according to NM_002087.2, starting with A in ATG as nucleotide position 1) was detected in patient B01 who at the age of 57 years developed memory problems and language dysfunction. After examination by a neuropsychologist and speech therapist, the patient received the clinical subdiagnosis bvFTD (Table 4).…”

“…18 The p.Gly35Glufs*19 mutation is a deletion of one out of four consecutive cytosines, and three substitutions in this sequence have previously been reported, c.99C4A, c.99C4T and c.102C4T, indicating that this region is a possible hotspot for mutations. 18,[23][24][25]28 The family of patient A01 and the Karolinska family shared an B297 kbp common disease haplotype as shown by comparing the disease haplotypes in the respective families. However, because they do not share a SNP (rs3859268) located 883 bp away from the mutation, we suggest that the mutation has arisen twice or that the two families must be very distantly related.…”

“…[17][18][19] The two missense variations p.Arg432Cys and p.Arg433Trp have previously been reported in FTLD patients. 14,18,24,25 According to the in silico analysis, codon 432 is weakly conserved but there is a large physicochemical difference between Arg and Cys. This variation has previously been reported in two FTLD patients and was absent in 646 control individuals.…”

“…This variation has previously been reported in two FTLD patients and was absent in 646 control individuals. 24,25 Furthermore, the substitution was predicted by in silico analysis to disturb the structure or the proteolytic cleavage of the precursor protein GRN and thus affect its biological function. 25 In an in vitro study, it was observed that p.Arg432Cys resulted in reduced secretion of GRN.…”

“…24,25 Furthermore, the substitution was predicted by in silico analysis to disturb the structure or the proteolytic cleavage of the precursor protein GRN and thus affect its biological function. 25 In an in vitro study, it was observed that p.Arg432Cys resulted in reduced secretion of GRN. 29 Moreover, there was a report of a patient with FTLD carrying p.Arg432Cys who had serum-GRN levels intermediate of controls and mutation carriers.…”