title: 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.
authors.affiliation: Department of Developmental Biology, Institut de Biologia Molecular de Barcelona IBMB-CSIC, Barcelona 08028, Spain.
authors.forename: Ariadna
authors.initials: A
authors.lastname: Laguna
authors.forename: María-José
authors.initials: MJ
authors.lastname: Barallobre
authors.forename: Miguel-Ángel
authors.initials: MÁ
authors.lastname: Marchena
authors.forename: Catarina
authors.initials: C
authors.lastname: Mateus
authors.forename: Erika
authors.initials: E
authors.lastname: Ramírez
authors.forename: Carmen
authors.initials: C
authors.lastname: Martínez-Cue
authors.forename: Jean M
authors.initials: JM
authors.lastname: Delabar
authors.forename: Miguel
authors.initials: M
authors.lastname: Castelo-Branco
authors.forename: Pedro
authors.initials: P
authors.lastname: de la Villa
authors.forename: Maria L
authors.initials: ML
authors.lastname: Arbonés
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D012160:Retina / Q000033:anatomy & histology* / Q000166:cytology / Q000201:enzymology; D055815:Young Adult; D000097603:Dyrk Kinases
chemical_list: D053453:Caspase 9; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases