@article{b7f8894c06244482b76ffdc23d029a85,
title = "Craniofacial dysmorphology in Down syndrome is caused by increased dosage of Dyrk1a and at least three other genes",
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.",
keywords = "Craniofacial development, Down syndrome, Dyrk1a, Morphometrics, Neural crest, Synchondroses",
author = "Yushi Redhead and Dorota Gibbins and Eva Lana-Elola and Sheona Watson-Scales and Lisa Dobson and Matthias Krause and Liu, {Karen J.} and Fisher, {Elizabeth M.C.} and Green, {Jeremy B.A.} and Tybulewicz, {Victor L.J.}",
note = "Funding Information: We thank Heather Cater and Sara Wells of the Mary Lyon Centre for breeding mice. We thank Alasdair Edgar for assistance with histology. The Francis Crick Institute receives its core funding from Cancer Research UK (CC2080), the UK Medical Research Council (CC2080) and the Wellcome Trust (CC2080). V.L.J.T. and E.M.C.F. were supported by the Wellcome Trust (098327 and 098328). V.L.J.T. was supported by the Francis Crick Institute. Y.R. was supported by a PhD studentship from the Francis Crick Institute and King{\textquoteright}s College London. J.B.A.G. was supported by King{\textquoteright}s College London. K.J.L. and M.K. were supported by the Biotechnology and Biological Sciences Research Council (BB/R015953/1). L.D. was supported by a Medical Research Council Doctoral Training Programme studentship. Open Access funding provided by the Francis Crick Institute. Deposited in PMC for immediate release. Publisher Copyright: {\textcopyright} 2023. Published by The Company of Biologists Ltd.",
year = "2023",
month = apr,
day = "26",
doi = "10.1242/dev.201077",
language = "English",
volume = "150",
journal = "Development (Cambridge)",
issn = "0950-1991",
publisher = "Company of Biologists Ltd",
number = "8",
}