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.

A novel phenotype in N-glycosylation disorders: Gillessen-Kaesbach–Nishimura skeletal dysplasia due to pathogenic variants in ALG9

“…Pathogenic variants in the ANK3 gene have been associated with autosomal recessive mental retardation 37. 16 The variant found in our patients was predicted to be deleterious by SIFT, AlignGVGD, Mutation Taster and PolyPhen. The parents were heterozygous carriers of this variant.…”

“…Pathogenic variants in the ANK3 gene have been associated with autosomal recessive mental retardation 37. 16 Neither skeletal dysplasia nor dysmorphic features were reported in the patients with autosomal mental retardation type 37, 16 indicating that the homozygous ANK3 variant most likely does not contribute to the congenital malformations in family 2.…”

Giant ankyrin-G: A critical innovation in vertebrate evolution of fast and integrated neuronal signaling

“…However, potential functions of the remaining 1,900 amino acids have not been examined. Interestingly, a frame-shift mutation in this region predicted to disrupt 480-kDa AnkG associates with severe cognitive disability in humans (41). mRNA levels of the 480-kDa AnkG isoform are dramatically reduced in lymphoblastoid cells, indicating that individuals homozygous for the mutation likely completely lack 480-kDa AnkG (41).…”

“…Interestingly, a frame-shift mutation in this region predicted to disrupt 480-kDa AnkG associates with severe cognitive disability in humans (41). mRNA levels of the 480-kDa AnkG isoform are dramatically reduced in lymphoblastoid cells, indicating that individuals homozygous for the mutation likely completely lack 480-kDa AnkG (41). Although these patients exhibit major intellectual disability (IQ < 50), hypotonia, spasticity, and severe behavioral problems, 480-kDa AnkG is not essential for viability.…”

Computational dissection of human episodic memory reveals mental process-specific genetic profiles

“…Some of them, e.g., ANK3 and NCAM1, also have been related to neurodevelopmental and psychiatric disorders (45) and to chronic stress-related cognitive disturbances (41).…”