Coexistence of variants in TBK1 and in other ALS-related genes elucidates an oligogenic model of pathogenesis in sporadic ALS

Serena Lattante, Paolo Niccolò Doronzio, Giuseppe Marangi, Amelia Conte, Giulia Bisogni, Daniela Bernardo, Tommaso Russo, Dante Lamberti, Sara Patrizi, Francesco Paolo Apollo, Christian Lunetta, Stefania Scarlino, Laura Pozzi, Marcella Zollino, Nilo Riva, Mario Sabatelli

Research output: Contribution to journalArticle

Abstract

Variants in tank-binding kinase 1 (TBK1) are responsible for a significant proportion of amyotrophic lateral sclerosis (ALS) cases. In the present study, we analyzed variants in TBK1 extracted by targeted sequencing of 32 genes in a group of 406 Italian patients with ALS. We identified 7 different TBK1 variants in 7 sporadic cases, resulting in a frequency of 1.7%. Three patients had missense variants (p.R357Q, p.R358H, and p.R724C), one patient had a small deletion (p.E618del), and 3 had truncating variants (p.Y482*, p.R229*, and p.N681*). Notably, we found that 4 patients had an additional variant in ALS-related genes: 2 in OPTN and 2 in the 3′UTR region of FUS. By studying an independent group of 7 TBK1-mutated patients previously reported, we found another variant in the 3′UTR region of FUS in one patient. The presence of a second variant in TBK1 variant carriers is an interesting finding that needs to be investigated in larger cohorts of patients. These findings suggest that TBK1 belongs to the category of genes conferring a significantly increased risk but not sufficient to cause disease.

Original languageEnglish
Pages (from-to)239.e9-239.e14
JournalNeurobiology of Aging
Volume84
DOIs
Publication statusPublished - Dec 2019

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Keywords

  • Amyotrophic lateral sclerosis
  • FUS
  • Oligogenicity
  • OPTN
  • TBK1

ASJC Scopus subject areas

  • Neuroscience(all)
  • Ageing
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

Cite this

Lattante, S., Doronzio, P. N., Marangi, G., Conte, A., Bisogni, G., Bernardo, D., Russo, T., Lamberti, D., Patrizi, S., Apollo, F. P., Lunetta, C., Scarlino, S., Pozzi, L., Zollino, M., Riva, N., & Sabatelli, M. (2019). Coexistence of variants in TBK1 and in other ALS-related genes elucidates an oligogenic model of pathogenesis in sporadic ALS. Neurobiology of Aging, 84, 239.e9-239.e14. https://doi.org/10.1016/j.neurobiolaging.2019.03.010