Triplication of DYRK1A causes retinal structural and functional alterations in Down syndrome

Abstract

Down syndrome (DS) results from the triplication of approximately 300 human chromosome 21 (Hsa21) genes and affects almost all body organs. Children with DS have defects in visual processing that may have a negative impact on their daily life and cognitive development. However, there is little known about the genes and pathogenesis underlying these defects. Here, we show morphometric in vivo data indicating that the neural retina is thicker in DS individuals than in the normal population. A similar thickening specifically affecting the inner part of the retina was also observed in a trisomic model of DS, the Ts65Dn mouse. Increased retinal size and cellularity in this model correlated with abnormal retinal function and resulted from an impaired caspase-9-mediated apoptosis during development. Moreover, we show that mice bearing only one additional copy of Dyrk1a have the same retinal phenotype as Ts65Dn mice and normalization of Dyrk1a gene copy number in Ts65Dn mice completely rescues both, morphological and functional phenotypes. Thus, triplication of Dyrk1a is necessary and sufficient to cause the retinal phenotype described in the trisomic model. Our data demonstrate for the first time the implication of DYRK1A overexpression in a developmental alteration of the central nervous system associated with DS, thereby providing insights into the aetiology of neurosensorial dysfunction in a complex disease.

Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID

“…23 DYRK1A has also been linked to retinal development in Drosophila and mouse models, which may relate to the observed retinal detachment in one of the individuals. 24–26 …”

DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies

“…7,9,34 Retino-cortical visual processing defects and body and wing size reduction are seen in both Dyrk1a ( ± ) and the mnb fly. 35,36 Dyrk1a-haploinsufficient mice show severe glucose intolerance and decreased beta cell proliferation. 37 Finally, in the Dyrk1a mouse and the mbn fly AKT-mediated insulin signaling pathway suppresses FOXO-mediated neuropeptide Y expression, which results in decreasing food intake.…”

Macular structural characteristics in children with Down syndrome

“…Our data showed that thickening could result from both inner and outer layers, which agrees with this report. However, Laguna et al investigated retinal morphology structure in a mouse model of Down syndrome and reported that only the inner layers contributed significantly to retinal thickening [38]. Furthermore, a significantly shallower foveal pit, which is often demonstrated in foveal hypoplasia [36], was present in the Down syndrome group compared with the control group.…”