Haplotype-specific MAPK3 expression in 16p11.2 deletion contributes to variable neurodevelopment

Author:

Liu Fang12,Liang Chen12,Li Zhengchang1,Zhao Sen3,Yuan Haiming4,Yao Ruen5,Qin Zailong6,Shangguan Shaofang1,Zhang Shujie6,Zou Li-Ping7ORCID,Chen Qian8,Gao Zhijie8,Wen Suiwen9,Peng Jing10,Yin Fei10,Chen Fei6,Qiu Xiaoxia6,Luo Jingsi6,Xie Yingjun1112,Lu Dian1112,Zhang Yu13,Xie Hua1,Li Guozhuang3,Zhang Terry Jianguo3,Luan Pengfei12,Wang Hongying14ORCID,Cui Xiaodai13,Huang Hailiang1516,Liu Ruize1516,Sun Xiaofang1112,Chen Chao17ORCID,Wu Nan3ORCID,Wang Jian5,Liu Chunyu1718ORCID,Shen Yiping5619ORCID,Gusella James F2021ORCID,Chen Xiaoli12ORCID

Affiliation:

1. Department of Medical Genetics, Capital Institute of Pediatrics , Beijing 100020 , China

2. Department of Medical Genetics, Graduate School of Peking Union Medical College , Beijing 100730 , China

3. The Department of Orthopedic Surgery, Key Laboratory of Big Data for Spinal Deformities, Beijing Key Laboratory for Genetic Research of Skeletal Deformity, State Key Laboratory of Complex Severe and Rare Diseases, all at Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences , Beijing 100730 , China

4. Affiliated Dongguan Maternal and Child Health Care Hospital, Southern Medical University , Dongguan 523120 , China

5. Department of Medical Genetics, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine , Shanghai 200127 , China

6. Genetic and Metabolic Central Laboratory, Birth Defects Prevention and Control Institute of Guangxi Zhuang Autonomous Region, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region , Nanning 530003 , China

7. Department of Pediatrics, Chinese PLA General Hospital , Beijing 100039 , China

8. Department of Neurology, The affiliated hospital of Capital Institute of Pediatrics , Beijing 100020 , China

9. Department of Obstetrics, Qingyuan People’s Hospital, 6th Hospital of Guangzhou Medical University , Qingyuan 511518 , China

10. Department of Pediatrics, Xiangya Hospital of Central South University, Hunan Intellectual and Developmental Disabilities Research Center , Changsha 410008 , China

11. Department of Obstetrics and Gynecology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University , Guangzhou 510150 , China

12. Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University , Guangzhou 510150 , China

13. Department of Lab Center, Capital Institute of Pediatrics , Beijing 100020 , China

14. Department of Clinical Laboratory, Children's Hospital of Soochow University , Suzhou 215000 , China

15. Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital , Boston, MA 02114 , USA

16. Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard , Cambridge, MA 02142 , USA

17. Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University , Changsha, 410083 , China

18. Department of Psychiatry, SUNY Upstate Medical University , Syracuse, NY 13201 , USA

19. Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School , Boston, MA 02115 , USA

20. Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital , Boston, MA 02114 , USA

21. Blavatnik Institute, Department of Genetics, Harvard Medical School , Boston, MA 02115 , USA

Abstract

Abstract Recurrent proximal 16p11.2 deletion (16p11.2del) is a risk factor for diverse neurodevelopmental disorders with incomplete penetrance and variable expressivity. Although investigation with human induced pluripotent stem cell models has confirmed disruption of neuronal development in 16p11.2del neuronal cells, which genes are responsible for abnormal cellular phenotypes and what determines the penetrance of neurodevelopmental abnormalities are unknown. We performed haplotype phasing of the 16p11.2 region in a 16p11.2del neurodevelopmental disorders cohort and generated human induced pluripotent stem cells for two 16p11.2del families with distinct residual haplotypes and variable neurodevelopmental disorder phenotypes. Using transcriptomic profiles and cellular phenotypes of the human induced pluripotent stem cell-differentiated cortex neuronal cells, we revealed MAPK3 to be a contributor to dysfunction in multiple pathways related to early neuronal development, with altered soma and electrophysiological properties in mature neuronal cells. Notably, MAPK3 expression in 16p11.2del neuronal cells varied on the basis of a 132 kb 58 single nucleotide polymorphism (SNP) residual haplotype, with the version composed entirely of minor alleles associated with reduced MAPK3 expression. Ten SNPs on the residual haplotype were mapped to enhancers of MAPK3. We functionally validated six of these SNPs by luciferase assay, implicating them in the residual haplotype-specific differences in MAPK3 expression via cis-regulation. Finally, the analysis of three different cohorts of 16p11.2del subjects showed that this minor residual haplotype is associated with neurodevelopmental disorder phenotypes in 16p11.2del carriers.

Funder

Beijing Natural Science Foundation

National Natural Science Foundation of China

Capital Health Research and Development of Special

Research Foundation

PUMCH

CAMS

Publisher

Oxford University Press (OUP)

Subject

Neurology (clinical)

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