Novel splicing mutation in the progranulin gene causing familial corticobasal syndrome

Abstract

Corticobasal syndrome (CBS) is a rare cognitive and movement disorder characterized by asymmetric rigidity, apraxia, alien-limb phenomenon, cortical sensory loss, myoclonus, focal dystonia, and dementia. It occurs along the clinical spectrum of frontotemporal lobar degeneration (FTLD), which has recently been shown to segregate with truncating mutations in progranulin (PGRN), a multifunctional growth factor thought to promote neuronal survival. This study identifies a novel splice donor site mutation in the PGRN gene (IVS7+1G-->A) that segregates with CBS in a Canadian family of Chinese origin. We confirmed the absence of the mutant PGRN allele in the RT-PCR product which supports the model of haploinsufficiency for PGRN-linked disease. This report of mutation in the PGRN gene in CBS extends the evidence for genetic and phenotypic heterogeneity in FTLD spectrum disorders.

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

“…18,20,23,24 The p.Gly35Glufs*19 identified in patient A01 has been reported in the Swedish Karolinska family, 23 as well as in two FTLD patients, one from the United States and one from Sweden. 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.…”

“…[14][15][16] Mutations in GRN have been reported in different clinical phenotypes including Alzheimer disease (AD) and corticobasal syndrome (CBS). [17][18][19][20] In FTLD-ALS and ALS patients, the role of GRN is unclear because only missense variations with unclear pathogenicity have been detected. 21,22 In order to investigate the GRN-mutation frequency in FTLD patients recruited from an outpatient memory clinic in Stockholm, Sweden, we have sequenced GRN and measured serum-GRN levels.…”

Molecular characterization of novel progranulin (GRN) mutations in frontotemporal dementia

“…Based on brain and lymphoblastoid GRN cDNA analysis, most of the mutations described so far are predicted to cause functional loss of GRN through NMD Cruts et al, 2006;Masellis et al, 2006].…”

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

“…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].…”