CHMP2B C-truncating mutations in frontotemporal lobar degeneration are associated with an aberrant endosomal phenotype in vitro
| Autor: | Marc Bruyland, Julie van der Zee, Bart Dermaut, Christine Van Broeckhoven, Patrick Santens, Peter Paul De Deyn, Elizabeth M. C. Fisher, Adrian M. Isaacs, Sebastiaan Engelborghs, Rik Vandenberghe, Karin Peeters, Hazel Urwin, Tim De Pooter, John Collinge |
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| Přispěvatelé: | Clinical sciences, Neurology |
| Rok vydání: | 2007 |
| Předmět: |
Male
ESCRT-III DNA Mutational Analysis Nonsense mutation Mutation Missense Nerve Tissue Proteins CHROMOSOME-3 Endosomes Biology DIAGNOSIS Transfection medicine.disease_cause DISEASE Neurons/cytology Exon DOMAIN Cell Line Tumor Genetics medicine CRITERIA Humans Nerve Tissue Proteins/genetics Missense mutation Molecular Biology Genetics (clinical) Neurons Medicine(all) Mutation COMPLEX Endosomal Sorting Complexes Required for Transport Dementia/genetics DEMENTIA Biology and Life Sciences PROGRESSIVE SUPRANUCLEAR PALSY Endosomes/metabolism General Medicine Frontotemporal lobar degeneration Charged multivesicular body protein 2B medicine.disease Pedigree Mutagenesis Site-Directed Mutation testing CORTICOBASAL DEGENERATION Dementia Female mutation Frontotemporal dementia |
| Zdroj: | HUMAN MOLECULAR GENETICS Human molecular genetics |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddm309 |
| Popis: | The charged multivesicular body protein 2B gene (CHMP2B) was recently associated with frontotemporal lobar degeneration (FTLD) linked to chromosome 3 in a Danish FTLD family (FTD-3). In this family, a mutation in the acceptor splice site of exon 6 produced two aberrant transcripts predicting two C-truncated CHMP2B proteins due to a read through of intron 5 (p.Met178ValfsX2) and a cryptic splicing event within exon 6 (p.Met178LeufsX30). Extensive mutation analysis of CHMP2B in Belgian patients (N = 146) identified one nonsense mutation in exon 5 (c.493C > T) in a familial FTLD patient, predicting a C-truncated protein p.Gln165X analogous to the Danish mutant proteins. Overexpression of Belgian p.Gln165X in human neuroblastoma SK-N-SH cells showed the formation of large, aberrant endosomal structures that were highly similar to those observed for Danish p.Met178ValfsX2. Together, these data suggest that C-truncating mutations in CHMP2B might underlie the pathogenic mechanism in FTLD by disturbing endosome function. We also describe a missense mutation in exon 5 of CHMP2B (p.Asn143Ser) in a familial patient with cortical basal degeneration. However, the pathogenic character of this mutation remains elusive. |
| Databáze: | OpenAIRE |
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