Co-occurring WARS2 and CHRNA6 mutations in a child with a severe form of infantile parkinsonism

01 Pubblicazione su rivista
Martinelli Simone, Cordeddu Viviana, Galosi Serena, Lanzo Ambra, Palma Eleonora, Pannone Luca, Ciolfi Andrea, Di Nottia Michela, Rizza Teresa, Bocchinfuso Gianfranco, Traversa Alice, Caputo Viviana, Farrotti Andrea, Carducci Claudia, Bernardini Laura, Cogo Susanna, Paglione Maria, Venditti Martina, Bentivoglio Annarita, Ng Joanne, Kurian Manju A, Civiero Laura, Greggio Elisa, Stella Lorenzo, Trettel Flavia, Sciaccaluga Miriam, Roseti Cristina, Carrozzo Rosalba, Fucile Sergio, Limatola Cristina, Di Schiavi Elia, Tartaglia Marco, Leuzzi Vincenzo
ISSN: 1873-5126

Objective: To investigate the molecular cause(s) underlying a severe form of infantile-onset parkinsonism and characterize functionally the identified variants.

Methods: A trio-based whole exome sequencing (WES) approach was used to identify the candidate variants underlying the disorder. In silico modeling, and in vitro and in vivo studies were performed to explore the impact of these variants on protein function and relevant cellular processes.

Results: WES analysis identified biallelic variants in WARS2, encoding the mitochondrial tryptophanyl tRNA synthetase (mtTrpRS), a gene whose mutations have recently been associated with multiple neurological phenotypes, including childhood-onset, levodopa-responsive or unresponsive parkinsonism in a few patients. A substantial reduction of mtTrpRS levels in mitochondria and reduced OXPHOS function was demonstrated, supporting their pathogenicity. Based on the infantile-onset and severity of the phenotype, additional variants were considered as possible genetic modifiers. Functional assessment of a selected panel of candidates pointed to a de novo missense mutation in CHRNA6, encoding the α6 subunit of neuronal nicotinic receptors, which are involved in the cholinergic modulation of dopamine release in the striatum, as a second event likely contributing to the phenotype. In silico, in vitro (Xenopus oocytes and GH4C1 cells) and in vivo (C. elegans) analyses demonstrated the disruptive effects of the mutation on acetylcholine receptor structure and function.

Conclusion: Our findings consolidate the association between biallelic WARS2 mutations and movement disorders, and suggest CHRNA6 as a genetic modifier of the phenotype.

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