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Craniofacial dysmorphology in Down syndrome is caused by increased dosage of Dyrk1a and at least three other genes

Redhead, Yushi; Gibbins, Dorota; Lana-Elola, Eva; Watson-Scales, Sheona; Dobson, Lisa; Krause, Matthias; Liu, Karen J; ... Tybulewicz, Victor LJ; + view all (2023) Craniofacial dysmorphology in Down syndrome is caused by increased dosage of Dyrk1a and at least three other genes. Development , 150 (8) , Article dev201077. 10.1242/dev.201077. Green open access

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Abstract

Down syndrome (DS), trisomy of human chromosome 21 (Hsa21), occurs in 1 in 800 live births and is the most common human aneuploidy. DS results in multiple phenotypes, including craniofacial dysmorphology, which is characterised by midfacial hypoplasia, brachycephaly and micrognathia. The genetic and developmental causes of this are poorly understood. Using morphometric analysis of the Dp1Tyb mouse model of DS and an associated mouse genetic mapping panel, we demonstrate that four Hsa21-orthologous regions of mouse chromosome 16 contain dosage-sensitive genes that cause the DS craniofacial phenotype, and identify one of these causative genes as Dyrk1a. We show that the earliest and most severe defects in Dp1Tyb skulls are in bones of neural crest (NC) origin, and that mineralisation of the Dp1Tyb skull base synchondroses is aberrant. Furthermore, we show that increased dosage of Dyrk1a results in decreased NC cell proliferation and a decrease in size and cellularity of the NC-derived frontal bone primordia. Thus, DS craniofacial dysmorphology is caused by an increased dosage of Dyrk1a and at least three other genes.

Type: Article
Title: Craniofacial dysmorphology in Down syndrome is caused by increased dosage of Dyrk1a and at least three other genes
Open access status: An open access version is available from UCL Discovery
DOI: 10.1242/dev.201077
Publisher version: https://doi.org/10.1242/dev.201077
Language: English
Additional information: This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
Keywords: Down syndrome, Craniofacial development, Dyrk1a, Neural crest, Morphometrics, Synchondroses
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10169257
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