Functional Dissection of CNVs in Neurodevelopmental Traits

神经发育特征中 CNV 的功能剖析

• 批准号: 10700047
• 负责人: Erica Ellen Davis
• 金额: $ 49.85万
• 依托单位: LURIE CHILDREN'S HOSPITAL OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10700047
• 关键词: 16p11.2; 19p13.1; Acceleration; Affect; Animal Model; Area; Attention; Biological; Biological Assay; Biology; Cartilage; Cells; Collaborations; Complex; Copy Number Polymorphism; Data; Data Set; Disease; Disease susceptibility; Dissection; Equilibrium; Face; Funding; Gene Combinations; Gene Dosage; Gene Expression Profile; Genes; Genetic; Genetic Epistasis; Genetic Transcription; Genomics; Histone Deacetylase; Human; Human Pathology; Individual; Knowledge; Learning; Maps; Measures; Methods; Modeling; Molecular; Mus; Mutation; Neuroanatomy; Neurodevelopmental Disorder; Neurons; Pathogenicity; Pathology; Pathway Analysis; Pathway interactions; Pharmaceutical Preparations; Phenocopy; Phenotype; Physiological; Probability; Property; Protocols documentation; RORA gene; Rattus; Repressor Proteins; Role; Safety; Syndrome; Testing; Therapeutic; Therapeutic Intervention; Transcript; Transcription Repressor; Transcriptional Regulation; Translating; Validation; Work; Zebrafish; biological systems; burden of illness; candidate identification; cell type; combinatorial; craniofacial; craniofacial development; dosage; drug candidate; drug development; drug discovery; drug repurposing; efficacy testing; genetic architecture; genetic corepressor; genomic data; genomic locus; in vivo; inhibitor; model organism; neurodevelopment; novel; phenotypic data; safety testing; therapeutic candidate; therapeutic development; tool; trait; transcriptome; transcriptomics

Understanding the contribution of copy number variants (CNVs) to human pathology remains challenging, in part because of the complex and varied influence of loci within them. In some cases, a single dosage-sensitive locus drives pathology. In other examples, multiple genes contribute to phenotypes through additive effects and through complex genetic interactions. In the previous funding period, we focused on deletion syndromes and reciprocal CNVs and asked whether we could develop tools to aid the identification of driver genes. Progress in that work has informed several areas of pathology. For example, the identification of SIN3B as a driver of a non-recurrent 230 kb deletion on 19p13.1 that causes a complex neurodevelopmental phenotype reinforced the role of the Sin3/HDAC transcriptional corepressor complex in neurodevelopment and facilitated the identification of Mendelian mutations that phenocopy the CNV. In the case of the 17q24.2 CNV, we learned about the synthetic CNV phenotype likely caused by dosage imbalance of both BPTF and PSMD12. Finally, modeling of multiple phenotypes associated with the 16p11.2 CNV showed how: (a) key neurodevelopmental and craniofacial pathologies were conserved from humans, to mice, to rats, to zebrafish; (b) demonstrated discrete epistatic interactions between loci; and (c) generated a host of surrogate model organisms in which to perform both pathway analysis and drug discovery. Overall, the genetic and functional dissection of CNV exemplars has underscored three observations: (a) not all genes in a CNV are dosage sensitive (suspected, but now supported by experimental evidence); (b) some genes are dosage sensitive in one direction (gain, loss, but not both); and (c) non-driver genes can participate in distinct genetic interactions. The knowledge and experimental tools gained affords us the opportunity to expand our ambition. We still do not understand how intra-CNV combinatorial dosage influences phenotype, and whether the lessons learned from prior work are broadly generalizable. Moreover, given the non-trivial contribution of CNVs to disease burden, it is crucial that we pay attention to the development of therapeutic avenues. We propose three Aims: (1) We will dissect a unique set of CNVs, in which the phenotype is driven only by duplication to identify triplosensitive genes and ask whether disease susceptibility is driven by a threshold effect as a means to understanding why only a subset of human genes are dosage sensitive. (2) We will harness our existing zebrafish models to characterize the molecular properties of epistatic effects using the neuronal and facial cartilage phenotypes of the 16p11.2 CNV and ask whether we can detect epistasis at the level of transcriptional regulation. (3) We will combine our extensive repertoire of zebrafish models of CNV drivers with the Connectivity Map (CMap) Touchstone dataset and a newly developed safety/efficacy protocol to identify candidate therapeutics. Together, our studies will refine the genetic architecture of genomic disorders, inform the molecular basic of genetic interactions, and chart a systematic path toward therapeutics for neurodevelopmental traits.

理解拷贝数变异（CNVs）对人类病理的贡献仍然具有挑战性

项目成果

CSGALNACT1-congenital disorder of glycosylation: A mild skeletal dysplasia with advanced bone age.

CSGALNACT1-先天性糖基化障碍：骨龄较高的轻度骨骼发育不良。

• DOI: 10.1002/humu.23952
• 发表时间: 2020
• 期刊: Human mutation
• 影响因子: 3.9
• 作者: Mizumoto,Shuji;Janecke,AndreasR;Sadeghpour,Azita;Povysil,Gundula;McDonald,MarieT;Unger,Sheila;Greber-Platzer,Susanne;Deak,KristenL;Katsanis,Nicholas;Superti-Furga,Andrea;Sugahara,Kazuyuki;Davis,EricaE;Yamada,Shuhei;Vodopiutz,
• 通讯作者: Vodopiutz,

Mitochondrial Copy Number as a Biomarker for Autism?

线粒体拷贝数作为自闭症的生物标志物？

• DOI: 10.1542/peds.2016-0049
• 发表时间: 2016
• 期刊: Pediatrics
• 影响因子: 8
• 作者: Golzio,Christelle;Katsanis,Nicholas
• 通讯作者: Katsanis,Nicholas

Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy.

• DOI: 10.1038/s41467-022-34349-8
• 发表时间: 2022-11-04
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Grange, Laura J.;Reynolds, John J.;Ullah, Farid;Isidor, Bertrand;Shearer, Robert F.;Latypova, Xenia;Baxley, Ryan M.;Oliver, Antony W.;Ganesh, Anil;Cooke, Sophie L.;Jhujh, Satpal S.;McNee, Gavin S.;Hollingworth, Robert;Higgs, Martin R.;Natsume, Toyoaki;Khan, Tahir;Martos-Moreno, Gabriel A.;Chupp, Sharon;Mathew, Christopher G.;Parry, David;Simpson, Michael A.;Nahavandi, Nahid;Yuksel, Zafer;Drasdo, Mojgan;Kron, Anja;Vogt, Petra;Jonasson, Annemarie;Seth, Saad Ahmed;Gonzaga-Jauregui, Claudia;Brigatti, Karlla W.;Stegmann, Alexander P. A.;Kanemaki, Masato;Josifova, Dragana;Uchiyama, Yuri;Oh, Yukiko;Morimoto, Akira;Osaka, Hitoshi;Ammous, Zineb;Argente, Jesus;Matsumoto, Naomichi;Stumpel, Constance T. R. M.;Taylor, Alexander M. R.;Jackson, Andrew P.;Bielinsky, Anja-Katrin;Mailand, Niels;Le Caignec, Cedric;Davis, Erica E.;Stewart, Grant S.
• 通讯作者: Stewart, Grant S.

Haploinsufficiency of the Sin3/HDAC corepressor complex member SIN3B causes a syndromic intellectual disability/autism spectrum disorder.

Sin3/HDAC 辅阻遏物复合体成员 SIN3B 的单倍体不足会导致综合征性智力障碍/自闭症谱系障碍。

• DOI: 10.1016/j.ajhg.2021.03.017
• 发表时间: 2021
• 期刊: American journal of human genetics
• 影响因子: 9.8
• 作者: Latypova,Xenia;Vincent,Marie;Mollé,Alice;Adebambo,OluwadamilareA;Fourgeux,Cynthia;Khan,TahirN;Caro,Alfonso;Rosello,Monica;Orellana,Carmen;Niyazov,Dmitriy;Lederer,Damien;Deprez,Marie;Capri,Yline;Kannu,Peter;Tabet,AnneClaude

Zebrafish knockout of Down syndrome gene, DYRK1A, shows social impairments relevant to autism.

• DOI: 10.1186/s13229-017-0168-2
• 发表时间: 2017
• 期刊: Molecular autism
• 影响因子: 6.2
• 作者: Kim OH;Cho HJ;Han E;Hong TI;Ariyasiri K;Choi JH;Hwang KS;Jeong YM;Yang SY;Yu K;Park DS;Oh HW;Davis EE;Schwartz CE;Lee JS;Kim HG;Kim CH
• 通讯作者: Kim CH