Migliavacca Eugenia, Golzio Christelle, Männik Katrin, Blumenthal Ian, Oh Edwin C, Harewood Louise, Kosmicki Jack A, Loviglio Maria Nicla, Giannuzzi Giuliana, Hippolyte Loyse, Maillard Anne M, Alfaiz Ali Abdullah, van Haelst Mieke M, Andrieux Joris, Gusella James F, Daly Mark J, Beckmann Jacques S, Jacquemont Sébastien, Talkowski Michael E, Katsanis Nicholas, Reymond Alexandre
Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics (SIB), 1015 Lausanne, Switzerland.
Center for Human Disease Modeling and Department of Cell Biology, Duke University, Durham, NC 27710, USA.
Am J Hum Genet. 2015 May 7;96(5):784-96. doi: 10.1016/j.ajhg.2015.04.002. Epub 2015 Apr 30.
The 16p11.2 600 kb copy-number variants (CNVs) are associated with mirror phenotypes on BMI, head circumference, and brain volume and represent frequent genetic lesions in autism spectrum disorders (ASDs) and schizophrenia. Here we interrogated the transcriptome of individuals carrying reciprocal 16p11.2 CNVs. Transcript perturbations correlated with clinical endophenotypes and were enriched for genes associated with ASDs, abnormalities of head size, and ciliopathies. Ciliary gene expression was also perturbed in orthologous mouse models, raising the possibility that ciliary dysfunction contributes to 16p11.2 pathologies. In support of this hypothesis, we found structural ciliary defects in the CA1 hippocampal region of 16p11.2 duplication mice. Moreover, by using an established zebrafish model, we show genetic interaction between KCTD13, a key driver of the mirrored neuroanatomical phenotypes of the 16p11.2 CNV, and ciliopathy-associated genes. Overexpression of BBS7 rescues head size and neuroanatomical defects of kctd13 morphants, whereas suppression or overexpression of CEP290 rescues phenotypes induced by KCTD13 under- or overexpression, respectively. Our data suggest that dysregulation of ciliopathy genes contributes to the clinical phenotypes of these CNVs.
16p11.2 600 kb拷贝数变异（CNV）与体重指数、头围和脑容量的镜像表型相关，是自闭症谱系障碍（ASD）和精神分裂症中常见的基因损伤。在此，我们研究了携带相互16p11.2 CNV个体的转录组。转录扰动与临床内表型相关，并富集了与ASD、头部大小异常和纤毛病相关的基因。在直系同源小鼠模型中，纤毛基因表达也受到干扰，这增加了纤毛功能障碍导致16p11.2病理的可能性。为支持这一假设，我们在16p11.2重复小鼠的CA1海马区发现了结构性纤毛缺陷。此外，通过使用已建立的斑马鱼模型，我们展示了16p11.2 CNV镜像神经解剖表型的关键驱动因子KCTD13与纤毛病相关基因之间的遗传相互作用。BBS7的过表达挽救了kctd13 morphants的头部大小和神经解剖缺陷，而CEP290的抑制或过表达分别挽救了KCTD13低表达或过表达诱导的表型。我们的数据表明，纤毛病基因的失调导致了这些CNV的临床表型。
