Disruption of a novel member of a sodium/hydrogen exchanger family and DOCK3 is associated with an attention deficit hyperactivity disorder-like phenotype

Abstract

Background: Attention deficit hyperactivity disorder (ADHD) is a complex condition with high heritability. However, both biochemical investigations and association and linkage studies have failed to define fully the underlying genetic factors associated with ADHD. We have identified a family co-segregating an early onset behavioural/developmental condition, with features of ADHD and intellectual disability, with a pericentric inversion of chromosome 3, 46N inv(3)(p14:q21). Methods: We hypothesised that the inversion breakpoints affect a gene or genes that cause the observed phenotype. Large genomic clones (P1 derived/yeast/bacterial artificial chromosomes) were assembled into contigs across the two inversion breakpoints using molecular and bioinformatic technologies. Restriction fragments crossing the junctions were identified by Southern analysis and these fragments were amplified using inverse PCR. Results: The amplification products were subsequently sequenced to reveal that the breakpoints lay within an intron of the dedicator of cytokinesis 3 (DOCK3) gene at the p arm breakpoint, and an intron of a novel member of the solute carrier family 9 (sodium/hydrogen exchanger) isoform 9 (SLC9A9) at the q arm. Both genes are expressed in the brain, but neither of the genes has previously been implicated in developmental or behavioural disorders. Conclusion: These two disrupted genes are candidates for involvement in the pathway leading to the neuropsychological condition in this family.

Dock3 Stimulates Axonal Outgrowth via GSK-3β-Mediated Microtubule Assembly

“…For example, the Val66Met functional polymorphism in human BDNF is involved in the pathogenesis of attention-deficit hyperactivity disorder (ADHD) (Egan et al, 2003;Friedel et al, 2005;Kent et al, 2005). Interestingly, a pericentric inversion breakpoint in the DOCK3 gene has been described in ADHD patients (de Silva et al, 2003), suggesting a possible link between the BDNF-Dock3 pathway and ADHD. On the other hand, GSK-3␤ activity has been associated with many psychiatric and neurodegenerative diseases, such as Alzheimer's disease, schizophrenia and autism spectrum disorders, and it has become increasingly apparent that GSK-3␤ might be a common therapeutic target for different classes of psychiatric drugs (Hur and Zhou, 2010).…”

Dock3 regulates BDNF‐TrkB signaling for neurite outgrowth by forming a ternary complex with Elmo and RhoG

“…For example, Val66Met functional polymorphism in human BDNF is involved in the pathogenesis of attentiondeficit hyperactivity disorder (ADHD) (Egan et al 2003;Friedel et al 2005;Kent et al 2005). Interestingly, a pericentric inversion breakpoint in the DOCK3 gene has been described in ADHD patients (de Silva et al 2003). Thus, disruption of the BDNFDock3 signaling may have therapeutic benefits to various neurodevelopmental disorders.…”

Traditional and emerging roles for the SLC9 Na+/H+ exchangers

“…By genetic approaches, NHE9 was linked to attention-deficit hyperactivity disorder (ADHD), addiction and mental retardation [37,102,153,109]. Several rare nonsense and missense mutations not found otherwise in asymptomatic individuals were described in affected patients.…”