Homozygous and heterozygous disruptions of ANK3: at the crossroads of neurodevelopmental and psychiatric disorders

• Published in: Human molecular genetics 2013-05, Vol.22 (10), p.1960-1970
• Main Authors: Iqbal, Zafar, Vandeweyer, Geert, van der Voet, Monique, Waryah, Ali Muhammad, Zahoor, Muhammad Yasir, Besseling, Judith A, Roca, Laura Tomas, Vulto-van Silfhout, Anneke T, Nijhof, Bonnie, Kramer, Jamie M, Van der Aa, Nathalie, Ansar, Muhammad, Peeters, Hilde, Helsmoortel, Céline, Gilissen, Christian, Vissers, Lisenka E L M, Veltman, Joris A, de Brouwer, Arjan P M, Frank Kooy, R, Riazuddin, Sheikh, Schenck, Annette, van Bokhoven, Hans, Rooms, Liesbeth
• Format: Article
• Language: English
• Subjects: Adult; Animals; Ankyrins - genetics; Disease Models, Animal; Drosophila; Drosophila melanogaster; Female; Frameshift Mutation; Gene Knockdown Techniques; Heterozygote; Homozygote; Humans; Infant; Male; Mental Disorders - genetics; Neurogenesis - genetics; Sleep Wake Disorders - genetics
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddt043

AnkyrinG, encoded by the ANK3 gene, is involved in neuronal development and signaling. It has previously been implicated in bipolar disorder and schizophrenia by association studies. Most recently, de novo missense mutations in this gene were identified in autistic patients. However, the causative nature of these mutations remained controversial. Here, we report inactivating mutations in the Ankyrin 3 (ANK3) gene in patients with severe cognitive deficits. In a patient with a borderline intelligence, severe attention deficit hyperactivity disorder (ADHD), autism and sleeping problems, all isoforms of the ANK3 gene, were disrupted by a balanced translocation. Furthermore, in a consanguineous family with moderate intellectual disability (ID), an ADHD-like phenotype and behavioral problems, we identified a homozygous truncating frameshift mutation in the longest isoform of the same gene, which represents the first reported familial mutation in the ANK3 gene. The causality of ANK3 mutations in the two families and the role of the gene in cognitive function were supported by memory defects in a Drosophila knockdown model. Thus we demonstrated that ANK3 plays a role in intellectual functioning. In addition, our findings support the suggested association of ANK3 with various neuropsychiatric disorders and illustrate the genetic and molecular relation between a wide range of neurodevelopmental disorders.