Myo9b mutations are associated with altered dendritic cell functions and increased susceptibility to autoimmune diabetes onset

Jing Zhang; Yuan Zou; Longmin Chen; Fei Sun; Qianqian Xu; Qing Zhou; Yi Wang; Xi Luo; Na Wang; Yang Li; Shu Zhang; Fei Xiong; Ping Yang; Shiwei Liu; Tao Yang; Jianping Weng; Décio L Eizirik; Jinhua Yan; Zhiguang Zhou; Cong-Yi Wang

doi:10.1038/s41467-023-41534-w

Myo9b mutations are associated with altered dendritic cell functions and increased susceptibility to autoimmune diabetes onset

Nat Commun. 2023 Sep 25;14(1):5977. doi: 10.1038/s41467-023-41534-w.

Authors

Jing Zhang^#¹, Yuan Zou^#¹, Longmin Chen^#^{1

2}, Fei Sun¹, Qianqian Xu¹, Qing Zhou¹, Yi Wang¹, Xi Luo¹, Na Wang¹, Yang Li¹, Shu Zhang¹, Fei Xiong¹, Ping Yang¹, Shiwei Liu³, Tao Yang⁴, Jianping Weng⁵, Décio L Eizirik⁶, Jinhua Yan⁷, Zhiguang Zhou⁸, Cong-Yi Wang⁹

Affiliations

¹ Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
² Department of Rheumatology and Immunology, the Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
³ Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China.
⁴ Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
⁵ Department of Endocrinology, the First Affiliated Hospital, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
⁶ ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium.
⁷ Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. yanjh79@163.com.
⁸ Diabetes Center, the Second Xiangya Hospital, Institute of Metabolism and Endocrinology, Central South University, Changsha, China. zhouzhiguang@csu.edu.cn.
⁹ Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. wangcy@tjh.tjmu.edu.cn.

^# Contributed equally.

Abstract

The regulation of autoimmunity against pancreatic islet β cells for type 1 diabetes (T1D) onset is still unclear. NOD/ShiLtJ (NOD) mice are prone to the onset of autoimmune diabetes, but its congenic strain, ALR/Lt (ALR), is not. Here we show that dendritic cells (DC) in ALR mice have impaired migratory and T-cell priming capability. Genomic comparative analysis maps a 33-bp deletion in the ALR Myosin IXb (Myo9b) gene when compared with NOD genome; meanwhile, data from knock-in models show that this ALR Myo9b allele impairs phenotypic and functional maturation of DCs, and prevents the development and progression of spontaneous autoimmune diabetes in NOD mice. In parallel, while the ALR 33-bp deletion of Myo9b is not conserved in human, we find a MYO9B R133Q polymorphism associating with increased risk of T1D and enhanced DC function in patients with T1D. Our results thus hint that alterations in Myo9b may contribute to altered DC function and autoimmune diabetes onset.

Publication types

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

MeSH terms

Alleles
Animals
Dendritic Cells*
Diabetes Mellitus, Type 1* / genetics
Humans
Mice
Mice, Inbred NOD
Mutation
Myosins* / genetics

Substances

myosin IXB
Myosins