Centre for Craniofacial Biology and Regenerative Biology, King's College London, London SE1 9RT, UK.
The Francis Crick Institute, London NW1 1AT, UK.
Development. 2023 Apr 15;150(8). doi: 10.1242/dev.201077. Epub 2023 Apr 26.
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.
唐氏综合征（DS），即人类 21 号染色体三体（Hsa21），在活产儿中发病率为 1/800，是最常见的人类非整倍体疾病。DS 会导致多种表型，包括颅面畸形，其特征为中面部发育不良、短头畸形和小下颌。其遗传和发育原因尚未完全清楚。通过对 Dp1Tyb 唐氏综合征小鼠模型和相关的小鼠遗传图谱进行形态计量学分析，我们证明了小鼠 16 号染色体上的四个 Hsa21 同源区域含有剂量敏感基因，这些基因导致了 DS 的颅面表型，并确定其中一个致病基因为 Dyrk1a。我们发现 Dp1Tyb 颅骨中最早和最严重的缺陷是神经嵴（NC）起源的骨骼，并且 Dp1Tyb 颅底骺软骨的矿化是异常的。此外，我们发现 Dyrk1a 基因剂量的增加导致 NC 细胞增殖减少，以及由 NC 衍生的额骨原基体积和细胞数量减少。因此，DS 的颅面畸形是由 Dyrk1a 基因和至少三个其他基因的剂量增加引起的。
