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

Author:

Redhead Yushi12,Gibbins Dorota2,Lana-Elola Eva2,Watson-Scales Sheona2,Dobson Lisa13,Krause Matthias3ORCID,Liu Karen J.1ORCID,Fisher Elizabeth M. C.4ORCID,Green Jeremy B. A.1ORCID,Tybulewicz Victor L. J.2ORCID

Affiliation:

1. Centre for Craniofacial Biology and Regenerative Biology, King's College London 1 , London SE1 9RT , UK

2. The Francis Crick Institute 2 , London NW1 1AT , UK

3. Randall Centre for Cell and Molecular Biophysics, King's College London 3 , London SE1 1UL , UK

4. Institute of Neurology, University College London 4 , London WC1N 3BG , UK

Abstract

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.

Funder

Wellcome Trust

Biotechnology and Biological Sciences Research Council

Publisher

The Company of Biologists

Subject

Developmental Biology,Molecular Biology

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