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

Fang Liu; Chen Liang; Zhengchang Li; Sen Zhao; Haiming Yuan; Ruen Yao; Zailong Qin; Shaofang Shangguan; Shujie Zhang; Li-Ping Zou; Qian Chen; Zhijie Gao; Suiwen Wen; Jing Peng; Fei Yin; Fei Chen; Xiaoxia Qiu; Jingsi Luo; Yingjun Xie; Dian Lu; Yu Zhang; Hua Xie; Guozhuang Li; Terry Jianguo Zhang; Pengfei Luan; Hongying Wang; Xiaodai Cui; Hailiang Huang; Ruize Liu; Xiaofang Sun; Chao Chen; Nan Wu; Jian Wang; Chunyu Liu; Yiping Shen; James F Gusella; Xiaoli Chen

doi:10.1093/brain/awad071

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

Brain. 2023 Aug 1;146(8):3347-3363. doi: 10.1093/brain/awad071.

Authors

Fang Liu^{1

2}, Chen Liang^{1

2}, Zhengchang Li¹, Sen Zhao³, Haiming Yuan⁴, Ruen Yao⁵, Zailong Qin⁶, Shaofang Shangguan¹, Shujie Zhang⁶, Li-Ping Zou⁷, Qian Chen⁸, Zhijie Gao⁸, Suiwen Wen⁹, Jing Peng¹⁰, Fei Yin¹⁰, Fei Chen⁶, Xiaoxia Qiu⁶, Jingsi Luo⁶, Yingjun Xie^{11

12}, Dian Lu^{11

12}, Yu Zhang¹³, Hua Xie¹, Guozhuang Li³, Terry Jianguo Zhang³, Pengfei Luan^{1

2}, Hongying Wang¹⁴, Xiaodai Cui¹³, Hailiang Huang^{15

16}, Ruize Liu^{15

16}, Xiaofang Sun^{11

12}, Chao Chen¹⁷, Nan Wu³, Jian Wang⁵, Chunyu Liu^{17

18}, Yiping Shen^{5

6

19}, James F Gusella^{20

21}, Xiaoli Chen^{1

2}

Affiliations

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.

PMID: 36869767
DOI: 10.1093/brain/awad071

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.

Keywords: 16p11.2 deletion (16p11.2del); haplotype-specific expression of MAPK3; human iPSC; neuronal cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Differentiation
Chromosome Deletion*
Haplotypes
Humans
Induced Pluripotent Stem Cells*
Phenotype