mutations in Italian patients with amyotrophic lateral sclerosis: genetic and functional characterisation.
In: Journal of Neurology, Neurosurgery & Psychiatry, Jg. 88 (2017-10-01), Heft 10, S. 869-875
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Zugriff:
Background: TANK-binding kinase 1 (TBK1) gene has been recently identified as a causative gene of amyotrophic lateral sclerosis (ALS). Methods: We sequenced the TBK1 gene in a cohort of 154 Italian patients with ALS with unclear genetic aetiology. We subsequently assessed the pathogenic potential of novel identified TBK1 variants using functional in vitro studies: expression, targeting and activity were evaluated in patient-derived fibroblasts and in cells transfected with mutated-TBK1 plasmids. Results: We identified novel genomic TBK1 variants including two loss-of-function (LoF) (p.Leu59Phefs*16 and c.358+5G>A), two missense (p.Asp118Asn and p.Ile397Thr) and one intronic variant (c.1644-5_1644-2delAATA), in addition to two previously reported pathogenetic missense variants (p.Lys291Glu and p.Arg357Gln). Functional studies in patient-derived fibroblasts revealed that the c.358+5G>A causes aberrant pre-mRNA processing leading TBK1 haploinsufficiency. Biochemical studies in cellular models showed that the truncating variant p.Leu59Phefs*16 abolishes TBK1 protein expression, whereas the p.Asp118Asn variant severely impairs TBK1 phosphorylation activity. Conversely, the p.Ile397Thr variant displayed enhanced phosphorylation activity, whose biological relevance is not clear. Conclusion: The observed frequency of TBK1 LoF variants was 1.3% (2/154), increasing up to 3.2% (5/154) by taking into account also the functional missense variants that we were able to classify as potentially pathogenic, supporting the relevance of TBK1 in the Italian population with ALS. [ABSTRACT FROM AUTHOR]
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mutations in Italian patients with amyotrophic lateral sclerosis: genetic and functional characterisation.
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Autor/in / Beteiligte Person: | Pozzi, Laura ; Valenza, Fabiola ; Mosca, Lorena ; Dal Mas, Andrea ; Domi, Teuta ; Romano, Alessandro ; Tarlarini, Claudia ; Falzone, Yuri Matteo ; Tremolizzo, Lucio ; Sorarù, Gianni ; Cerri, Federica ; Ferraro, Pilar M. ; Basaia, Silvia ; Agosta, Federica ; Fazio, Raffaella ; Comola, Mauro ; Comi, Giancarlo ; Ferrari, Maurizio ; Quattrini, Angelo ; Lunetta, Christian |
Zeitschrift: | Journal of Neurology, Neurosurgery & Psychiatry, Jg. 88 (2017-10-01), Heft 10, S. 869-875 |
Veröffentlichung: | 2017 |
Medientyp: | academicJournal |
ISSN: | 0022-3050 (print) |
DOI: | 10.1136/jnnp-2017-316174 |
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