title: Homozygous and heterozygous disruptions of ANK3: at the crossroads of neurodevelopmental and psychiatric disorders.
abstract: 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.
authors: Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Donders Institute for Brain, Cognitionand Behaviour, Radboud University Medical Centre, Nijmegen, TheNetherlands.
authors: Zafar
authors: Z
authors: Iqbal
authors: Geert
authors: G
authors: Vandeweyer
authors: Monique
authors: M
authors: van der Voet
authors: Ali Muhammad
authors: AM
authors: Waryah
authors: Muhammad Yasir
authors: MY
authors: Zahoor
authors: Judith A
authors: JA
authors: Besseling
authors: Laura Tomas
authors: LT
authors: Roca
authors: Anneke T
authors: AT
authors: Vulto-van Silfhout
authors: Bonnie
authors: B
authors: Nijhof
authors: Jamie M
authors: JM
authors: Kramer
authors: Nathalie
authors: N
authors: Van der Aa
authors: Muhammad
authors: M
authors: Ansar
authors: Hilde
authors: H
authors: Peeters
authors: Céline
authors: C
authors: Helsmoortel
authors: Christian
authors: C
authors: Gilissen
authors: Lisenka E L M
authors: LE
authors: Vissers
authors: Joris A
authors: JA
authors: Veltman
authors: Arjan P M
authors: AP
authors: de Brouwer
authors: R
authors: R
authors: Frank Kooy
authors: Sheikh
authors: S
authors: Riazuddin
authors: Annette
authors: A
authors: Schenck
authors: Hans
authors: H
authors: van Bokhoven
authors: Liesbeth
authors: L
authors: Rooms
mesh_terms: D000328:Adult; D000818:Animals; D017487:Ankyrins / Q000235:genetics*; D004195:Disease Models, Animal; D004331:Drosophila melanogaster; D005260:Female; D016368:Frameshift Mutation; D055785:Gene Knockdown Techniques; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D001523:Mental Disorders / Q000235:genetics*; D055495:Neurogenesis / Q000235:genetics*; D012893:Sleep Wake Disorders / Q000235:genetics*
chemical_list: C490613:ANK3 protein, human; D017487:Ankyrins