We describe a new mutation in the PGRN gene (A303AfsX57) associated with late-onset frontotemporal dementia and with "cat's eye" shaped intranuclear and cytoplasmatic ubiquitin immunoreactive inclusions in the neuropathological exam. The A303AfsX57 mutation is consistent with a nucleotide deletion in exon 8 (c908delC). This deletion causes a frameshift at codon 303 that introduces a premature termination codon (A303AfsX57).
"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) [Cruts et al., 2006; 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) [Cruts et al., 2006; Baker et al., 2006; Huey et al., 2006; Pickering-Brown et al., 2006, 2008; Boeve 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) [Cruts et al., 2006; 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. "
[Show abstract][Hide abstract] ABSTRACT: Mutations in the gene encoding granulin (HUGO gene symbol GRN, also referred to as progranulin, PGRN), located at chromosome 17q21, were recently linked to tau-negative ubiquitin-positive frontotemporal lobar degeneration (FTLDU). Since then, 63 heterozygous mutations were identified in 163 families worldwide, all leading to loss of functional GRN, implicating a haploinsufficiency mechanism. Together, these mutations explained 5 to 10% of FTLD. The high mutation frequency, however, might still be an underestimation because not all patient samples were examined for all types of loss-of-function mutations and because several variants, including missense mutations, have a yet uncertain pathogenic significance. Although the complete phenotypic spectrum associated with GRN mutations is not yet fully characterized, it was shown that it is highly heterogeneous, suggesting the influence of modifying factors. A role of GRN in neuronal survival was suggested but the exact mechanism by which neurodegeneration and deposition of pathologic brain inclusions occur still has to be clarified.
Human Mutation 12/2008; 29(12):1373-86. DOI:10.1002/humu.20785 · 5.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Ubiquitin-positive, tau-negative, frontotemporal dementia (FTD) is caused by null mutations in progranulin (PGRN; HUGO gene symbol GRN), suggesting a haploinsufficiency mechanism. Since whole gene deletions also lead to the loss of a functional allele, we performed systematic quantitative analyses of PGRN in a series of 103 Belgian FTD patients. We identified in one patient (1%) a genomic deletion that was absent in 267 control individuals. The deleted segment was between 54 and 69 kb in length and comprised PGRN and two centromeric neighboring genes RPIP8 (HUGO gene symbol RUNDC3A) and SLC25A39. The patient presented clinically with typical FTD without additional symptoms, consistent with haploinsufficiency of PGRN being the only gene contributing to the disease phenotype. This study demonstrates that reduced PGRN in absence of mutant protein is sufficient to cause neurodegeneration and that previously reported PGRN mutation frequencies are underestimated.
Human Mutation 01/2008; 29(1):53-8. DOI:10.1002/humu.20651 · 5.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Great strides have been made in the last 2 years in the field of frontotemporal lobar degeneration (FTLD), particularly with respect to the genetics and molecular biology of FTLD with ubiquitinated inclusions. It is now clear that most cases of familial FTLD with ubiquitinated inclusions have mutations in the progranulin gene, located on chromosome 17. It is also clear that most ubiquitinated inclusions in FTLD with ubiquitinated inclusions are composed primarily of TAR DNA-binding protein-43. Thus, FTLDs can be separated into 2 major groups (i.e. tauopathies and ubiquitinopathies), and most of the ubiquitinopathies can now be defined as TAR DNA-binding protein-43 proteinopathies. Many of the familial FTLDs are linked to chromosome 17, including both the familial tauopathies and the familial TAR DNA-binding protein-43 proteinopathies with progranulin mutations. This review highlights the neuropathologic features and the most important discoveries of the last 2 years and places these findings into the historical context of FTLD.
Journal of Neuropathology and Experimental Neurology 07/2008; 67(7):635-48. DOI:10.1097/NEN.0b013e31817d751c · 3.80 Impact Factor
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