Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder.
Courraud J
et al.
Genet Med 2021 Nov;23(11)2150-2159
Courraud J, Chater-Diehl E, Durand B, Vincent M, Del Mar Muniz Moreno M, Boujelbene I, Drouot N, Genschik L, Schaefer E, Nizon M, Gerard B, Abramowicz M, Cogné B, Bronicki L, Burglen L, Barth M, Charles P, Colin E, Coubes C, David A, Delobel B, Demurger F, Passemard S, Denommé AS, Faivre L, Feger C, Fradin M, Francannet C, Genevieve D, Goldenberg A, Guerrot AM, Isidor B, Johannesen KM, Keren B, Kibæk M, Kuentz P, Mathieu-Dramard M, Demeer B, Metreau J, Steensbjerre Møller R, Moutton S, Pasquier L, Pilekær Sørensen K, Perrin L, Renaud M, Saugier P, Rio M, Svane J, Thevenon J, Tran Mau Them F, Tronhjem CE, Vitobello A, Layet V, Auvin S, Khachnaoui K, Birling MC, Drunat S, Bayat A, Dubourg C, El Chehadeh S, Fagerberg C, Mignot C, Guipponi M, Bienvenu T, Herault Y, Thompson J, Willems M, Mandel JL, Weksberg R, Piton A.
Genet Med 2021 Nov;23(11)2150-2159
Abstract: <h4>Purpose</h4>DYRK1A syndrome is among the most frequent monogenic forms of intellectual disability (ID). We refined the molecular and clinical description of this disorder and developed tools to improve interpretation of missense variants, which remains a major challenge in human genetics.<h4>Methods</h4>We reported clinical and molecular data for 50 individuals with ID harboring DYRK1A variants and developed (1) a specific DYRK1A clinical score; (2) amino acid conservation data generated from 100 DYRK1A sequences across different taxa; (3) in vitro overexpression assays to study level, cellular localization, and kinase activity of DYRK1A mutant proteins; and (4) a specific blood DNA methylation signature.<h4>Results</h4>This integrative approach was successful to reclassify several variants as pathogenic. However, we questioned the involvement of some others, such as p.Thr588Asn, still reported as likely pathogenic, and showed it does not cause an obvious phenotype in mice.<h4>Conclusion</h4>Our study demonstrated the need for caution when interpreting variants in DYRK1A, even those occurring de novo. The tools developed will be useful to interpret accurately the variants identified in the future in this gene.
MNB/DYRK1A as a multiple regulator of neuronal development.
Tejedor FJ
et al.
FEBS J 2011 Jan;278(2)223-235
Tejedor FJ, Hämmerle B.
FEBS J 2011 Jan;278(2)223-235
Abstract: MNB/DYRK1A is a member of the dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) family that has been strongly conserved across evolution. There are substantial data implicating MNB/DYRK1A in brain development and adult brain function, as well as in neurodegeneration and Down syndrome pathologies. Here we review our current understanding of the neurodevelopmental activity of MNB/DYRK1A. We discuss how MNB/DYRK1A fulfils several sequential roles in neuronal development and the molecular mechanisms possibly underlying these functions. We also summarize the evidence behind the hypotheses to explain how the imbalance in MNB/DYRK1A gene dosage might be implicated in the neurodevelopmental alterations associated with Down syndrome. Finally, we highlight some research directions that may help to clarify the mechanisms and functions of MNB/DYRK1A signalling in the developing brain.
Minibrain (MNBH) is a single copy gene mapping to human chromosome 21q22.2.
Guimera J
et al.
Cytogenet Cell Genet 1997 ;77(3-4)182-184
Guimera J, Pritchard M, Nadal M, Estivill X.
Cytogenet Cell Genet 1997 ;77(3-4)182-184
Abstract: We have identified a human homologue of the Drosophila mnb gene (MNBH) on chromosome 21, while another study mapped an EST clone (R38268) with similarity to minibrain to human chromosome 1. This report describes the mapping of MNBH to a single locus on human chromosome 21q22.2 by FISH and Southern blotting. Comparison of the similarities between the two sequences and mnb demonstrates that MNBH on chromosome 21 is the true human homologue of Drosophila mnb.
Cloning of a human homolog of the Drosophila minibrain/rat Dyrk gene from "the Down syndrome critical region" of chromosome 21.
Shindoh N
et al.
Biochem Biophys Res Commun 1996 Aug;225(1)92-99
Shindoh N, Kudoh J, Maeda H, Yamaki A, Minoshima S, Shimizu Y, Shimizu N.
Biochem Biophys Res Commun 1996 Aug;225(1)92-99
Abstract: To isolate genes responsible for some features of Down syndrome, we performed exon trapping experiments using a series of cosmid clones derived from "the Down syndrome critical region" of chromosome 21 and isolated six exons which are highly homologous to the sequence of Drosophila minibrain (mnb) gene. The Drosophila mnb gene encodes a serine/threonine protein kinase that is required in distinct neuroblast proliferation centers during postembryonic neurogenesis. Using one of these six exons as a probe, we isolated cDNA clones for human homolog of Drosophila mnb gene (MNB) from a fetal brain cDNA library. Human MNB cDNA encodes a protein of 754 amino acids with a nuclear targeting sequence and a catalytic domain common to the serine/threonine-specific protein kinase. The human MNB protein strikingly resembles the recently discovered rat Dyrk protein kinase with a dual specificity. The MNB mRNA is expressed in various tissues including fetal and adult brains. The remarkable similarity of human MNB protein to Drosophila mnb and rat Dyrk proteins implies that human MNB protein may play a significant role in a signaling pathway regulating nuclear functions of neuronal cell proliferation, contributing to certain features of Down syndrome.
