Biallelic Mutations in MYORG Cause Autosomal Recessive Primary Familial Brain Calcification

Xiang-Ping Yao¹, Xuewen Cheng², Chong Wang¹, Miao Zhao¹, Xin-Xin Guo¹, Hui-Zhen Su¹, Lu-Lu Lai¹, Xiao-Huan Zou¹, Xue-Jiao Chen³, Yuying Zhao⁴, En-Lin Dong¹, Ying-Qian Lu¹, Shuang Wu¹, Xiaojuan Li⁵, Gaofeng Fan⁵, Hongjie Yu⁶, Jianfeng Xu⁶, Ning Wang⁷, Zhi-Qi Xiong⁸, Wan-Jin Chen⁹

Affiliations

¹ Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China.
² Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
³ Department of Neurology, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou 363000, China.
⁴ Laboratory of Neuromuscular Disorders and Department of Neurology, Qilu Hospital, Shandong University, Jinan 250012, China.
⁵ School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
⁶ Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, IL 60201, USA.
⁷ Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China; Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou 350005, China. Electronic address: ningwang@fjmu.edu.cn.
⁸ Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: xiongzhiqi@ion.ac.cn.
⁹ Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China; Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou 350005, China. Electronic address: wanjinchen75@fjmu.edu.cn.

PMID: 29910000
DOI: 10.1016/j.neuron.2018.05.037

Free article

Biallelic Mutations in MYORG Cause Autosomal Recessive Primary Familial Brain Calcification

Xiang-Ping Yao et al. Neuron. 2018.

Free article

. 2018 Jun 27;98(6):1116-1123.e5.

doi: 10.1016/j.neuron.2018.05.037. Epub 2018 Jun 14.

Authors

Affiliations

¹ Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China.
² Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
³ Department of Neurology, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou 363000, China.
⁴ Laboratory of Neuromuscular Disorders and Department of Neurology, Qilu Hospital, Shandong University, Jinan 250012, China.
⁵ School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
⁶ Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, IL 60201, USA.
⁷ Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China; Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou 350005, China. Electronic address: ningwang@fjmu.edu.cn.
⁸ Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: xiongzhiqi@ion.ac.cn.
⁹ Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China; Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou 350005, China. Electronic address: wanjinchen75@fjmu.edu.cn.

PMID: 29910000
DOI: 10.1016/j.neuron.2018.05.037

Abstract

Primary familial brain calcification (PFBC) is a genetically heterogeneous disorder characterized by bilateral calcifications in the basal ganglia and other brain regions. The genetic basis of this disorder remains unknown in a significant portion of familial cases. Here, we reported a recessive causal gene, MYORG, for PFBC. Compound heterozygous or homozygous mutations of MYORG co-segregated completely with PFBC in six families, with logarithm of odds (LOD) score of 4.91 at the zero recombination fraction. In mice, Myorg mRNA was expressed specifically in S100β-positive astrocytes, and knockout of Myorg induced the formation of brain calcification at 9 months of age. Our findings provide strong evidence that loss-of-function mutations of MYORG cause brain calcification in humans and mice.

Keywords: MYORG; PFBC; astrocyte; brain calcification; glycosidase.

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Comment in

Biallelic MYORG mutations: Primary familial brain calcification goes recessive.
Alvarez-Fischer D, Westenberger A. Alvarez-Fischer D, et al. Mov Disord. 2019 Mar;34(3):322. doi: 10.1002/mds.27629. Epub 2019 Jan 24. Mov Disord. 2019. PMID: 30675931 No abstract available.
New homozygous indel in MYORG linked to brain calcification, thyroidopathy and neuropathy.
Ferreira LD, de Oliveira JRM. Ferreira LD, et al. Brain. 2019 Sep 1;142(9):e51. doi: 10.1093/brain/awz225. Brain. 2019. PMID: 31332435 No abstract available.

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Biallelic Mutations in MYORG Cause Autosomal Recessive Primary Familial Brain Calcification

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Biallelic Mutations in MYORG Cause Autosomal Recessive Primary Familial Brain Calcification

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