Cyclin-dependent Kinase 5: Novel role of gene variants identified in ADHD

Subhamita Maitra,Kanchan Mukhopadhyay,Mahasweta Chatterjee,Swagata Sinha

doi:10.1038/s41598-017-06852-2

Abstract

Cortical neuronal migration and formation of filamentous actin cytoskeleton, needed for development, normal cell growth and differentiation, are regulated by the cyclin-dependent kinase 5 (Cdk5). Attention deficit hyperactivity disorder (ADHD) is associated with delayed maturation of the brain and hence we hypothesized that cdk5 may have a role in ADHD. Eight functional CDK5 gene variants were analyzed in 848 Indo-Caucasoid individuals including 217 families with ADHD probands and 250 healthy volunteers. Only three variants, rs2069454, rs2069456 and rs2069459, predicted to affect transcription, were found to be bimorphic. Significant difference in rs2069456 “AC” genotype frequency was noticed in the probands, more specifically in the males. Family based analysis revealed over transmission of rs2069454 “C” and rs2069456 “A” to the probands. Quantitative trait analysis exhibited association of haplotypes with inattention, domain specific impulsivity, and behavioral problem, though no significant contribution was noticed on the age of onset of ADHD. Gene variants also showed significant association with cognitive function and co-morbidity. Probands having rs2069459 “TT” showed betterment during follow up. It may be inferred from this pilot study that CDK5 may affect ADHD etiology, possibly by attenuating synaptic neurotransmission and could be a useful target for therapeutic intervention.

Highlights

Attention deficit hyperactivity disorder (ADHD) is a developmental disorder often characterized by dysfunction of the synaptic system[1]
The Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase crucial for normal development[20], since absence of CDK5 leads to lethality[21]
Three genomic regions of CDK5 were analyzed by DNA sequencing

Summary

Introduction

Attention deficit hyperactivity disorder (ADHD) is a developmental disorder often characterized by dysfunction of the synaptic system[1]. The balance between cortical thickening during early childhood and cortical thinning during pubertal stage may be disrupted in ADHD patients[15] This may eventually lead to an altered over all brain activity and expression of ADHD associated symptoms. The primary motor cortex, which showed early maturation in ADHD probands as compared to typically developing children[15], was devoid of Cdk[5] expression during infancy, pubertal or adolescent stages (BGEE analysis). Association of different gene variants with endophenotypes of the probands including, sex, age of onset, inattention, hyperactivity, impulsivity, behavioral problem, co-morbid disorders and executive deficit, were analyzed in order to find out contribution of gene variants on these traits. Probands were re-assessed to find out association of the variants with persistence of the disease severity

Methods

Results

Conclusion