Autism-associated Dyrk1a truncation mutants impair neuronal dendritic and spine growth and interfere with postnatal cortical development

Abstract

Autism is a prevailing neurodevelopmental disorder with a large genetic/genomic component. Recently, the dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A) gene was implicated as a risk factor for autism spectrum disorder (ASD). We identified five DYRK1A variants in ASD patients and found that the dose of DYRK1A protein has a crucial role in various aspects of postnatal neural development. Dyrk1a loss of function and gain of function led to defects in dendritic growth, dendritic spine development and radial migration during cortical development. Importantly, two autism-associated truncations, R205X and E239X, were shown to be Dyrk1a loss-of-function mutants. Studies of the truncated Dyrk1a mutants may provide new insights into the role of Dyrk1a in brain development, as well as the role of Dyrk1a loss of function in the pathophysiology of autism.

Impaired development of neocortical circuits contributes to the neurological alterations in DYRK1A haploinsufficiency syndrome

“…A third possibility could be that they represent pathogenic variants of DYRK1A hyperactivity, based on the links of DYRK1A overexpression with certain DS pathological traits (Becker et al, 2014). Of note, the hyperactive G486D mutation was identified in a patient with macrocephaly (Dang et al, 2018), in contrast with the DHS patients with LoF mutations in which microcephaly is, generally, observed ( Supplementary Table 1). However, the results might also mean that these mutations do not provoke any negative effects.…”

“…However, the results might also mean that these mutations do not provoke any negative effects. Indeed, the effects of the catalytic missense A195T and L259F mutants have been evaluated in cultured cortical neurons, where their impact on neurite extension was similar to that of the WT neurons (Dang et al, 2018). Therefore, and for the catalytically active mutants, there is the possibility that the genetic variant in the DYRK1A gene is a benign variant and therefore not responsible for the clinical phenotype.…”

“…The amount of Dyrk1a protein in the mouse developing neocortex increases during neurogenesis, reaching maximum levels in late embryonic development and during the first postnatal week (Dang et al, 2018). At these developmental stages, neural precursors shift their status and become gliogenic (Kriegstein and Alvarez-Buylla, 2009), while neurons extend neurites and synaptogenesis begins (Li et al, 2010).…”

“…These mutations lead to the production of truncated DYRK1A proteins that lack partially o totally the kinase domain and that are therefore catalytically inactive. DYRK1A missense mutations have also been identified in patients with a distinctive DHS phenotype Dang et al, 2018;De Rubeis et al, 2014;Deciphering Developmental Disorders, 2015;Evers et al, 2017;Ji et al, 2015;Ruaud et al, 2015;Stessman et al, 2017;Trujillano et al, 2017;Zhang et al, 2015). The structural modeling of these mutations predicts that they are loss-of-function (LoF) mutations (Evers et al, 2017;Ji et al, 2015).…”

“…The structural modeling of these mutations predicts that they are loss-of-function (LoF) mutations (Evers et al, 2017;Ji et al, 2015). However, experimental data supporting this prediction have been reported only for a few of them (Dang et al, 2018;Widowati et al, 2018).…”