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

Abstract

Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative disease with an age at onset generally below 65 years. Mutations in progranulin (GRN) have been reported to be able to cause FTLD through haploinsufficiency. We have sequenced GRN in 121 patients with FTLD and detected six different mutations in eight patients: p.Gly35Glufs*19, p.Asn118Phefs*4, p.Val200Glyfs*18, p.Tyr294*, p.Cys404* and p.Cys416Leufs*30. Serum was available for five of the mutations, where the serum-GRN levels were found to be >50% reduced compared with FTLD patients without GRN mutations. Moreover, the p.Cys416Leufs*30 mutation segregated in an affected family with different dementia diagnoses. The mutation frequency of GRN mutation was 6.6% in our FTLD cohort.

Figure 1

Serum-GRN levels in 76 FTLD patients and four additional family members with or without GRN mutations (Karolinska family: p.Gly35Glufs*19 carrier and non-carrier; G01 family: p.Cys416Leufs*30 carrier and non-carrier). The horizontal line indicates the mean serum-GRN level (141 ng/ml) of patients without premature stop codons (n=70). The dashed lines represent one and two SD from the mean value, respectively.

Figure 2

Immunohistochemical staining of the frontal cortex with phospho-TDP-43 antibody on patient D01 (a–c) and G01 (d–f). Phospho-TDP-43-positive NCIs (arrows in figure a and d), neurites (arrows in figure b and e) and NIIs (arrows in figure c and f) were detected in both patients. Scale bar=20 μm.