Role of ANO3 mutations in dystonia: A large-scale mutational screening study

• Published in: Parkinsonism & related disorders Vol. 62; pp. 196 - 200
• Main Authors: Olschewski, Luisa, Jesús, Silvia, Kim, Han-Joon, Tunc, Sinem, Löns, Sebastian, Junker, Johanna, Zeuner, Kirsten E., Kühn, Andrea A., Kuhlenbäumer, Gregor, Schäffer, Eva, Berg, Daniela, Kasten, Meike, Ferbert, Andreas, Altenmüller, Eckart, Brüggemann, Norbert, Bauer, Peter, Rolfs, Arndt, Jeon, Beomseok, Bäumer, Tobias, Mir, Pablo, Klein, Christine, Lohmann, Katja
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.05.2019
• Subjects: Adult; Aged; ANO3; Anoctamins - genetics; De novo; Dystonia; Dystonia - diagnosis; Dystonia - genetics; Female; Genetic Testing - methods; Genetic Variation - genetics; Humans; Male; Middle Aged; Mutation - genetics; Pedigree; De novo; Dystonia; ANO3
• ISSN: 1353-8020; 1873-5126
• DOI: 10.1016/j.parkreldis.2018.12.030

The role of ANO3 variants as a monogenic cause of dystonia is still under debate because of its relatively high frequency also in controls. To screen >1000 patients with movement disorders for rare ANO3 variants. We searched for rare ANO3 variants in 729 dystonia and 294 Parkinson's disease (PD) patients using a gene panel. Variants were validated by Sanger sequencing. For one variant carrier, family members were available for segregation analysis. Nine carriers (seven with dystonia [1.0%], two with PD [0.7%]) of seven different rare, protein-changing variants were identified. None of these variants has been previously reported in dystonia patients. Two of the variants in dystonia patients were found recurrently: p.Arg328Cys was detected in two Korean and p.Arg969Gln in two German patients. The frequency of these two variants in our sample seemed to be higher as in ethnically matched samples from the Genome Aggregation Database (GnomAD). Further, we identified a patient with early-onset, generalized dystonia with a de-novo variant in ANO3 (p.Val561Glu). Of note, she benefitted from deep brain stimulation. This study confirms the relatively high frequency of rare, protein-changing ANO3 variants in both dystonia and non-dystonia patients indicating that not all variants contribute to the disease. Thus, disease relevance of novel variants remains difficult to interpret and functional studies are warranted for a better understanding of the role of ANO3 variants in dystonia. In contrast, de-novo variants in childhood-onset, generalized dystonia seem to represent an as yet underestimated phenotypic expression of changes in ANO3. •Large scale (>1000 patients) screening study for ANO3 mutations.•Identification of recurrent ANO3 variants supporting pathogenicity.•Identification of a de novo ANO3 variant supporting pathogenicity.•Good response to deep brain stimulation in the patient with the de-novo variant.