Ping Yu1, Yun Cui2, Wanshi Cai3, Honghu Wu1, Xiaoqiang Xiao1, Qianzhi Shao1, Liang Ma2, Sen Guo1, Nana Wu1, Zi-Bing Jin4, Yongjin Wang2, Tao Cai5, Zhong Sheng Sun1,3, Jia Qu4. 1. The Institute of Genomic Medicine, Wenzhou Medical University, Zhejiang, China. 2. Department of Ophthalmology, Heping Hospital, Changzhi Medical College, Shanxi, China. 3. Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China. 4. State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Wenzhou, Zhejiang, China. 5. Experimental Medicine Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA.
Abstract
PURPOSE: Genetic etiology of congenital/infantile nystagmus remains largely unknown. This study aimed to identify genomic mutations in patients with infantile nystagmus and an associated disease network. METHODS: Patients with inherited and sporadic infantile nystagmus were recruited for whole-exome and Sanger sequencing. β-Mannosidase activities were measured. Gene expression, protein-protein interaction, and nystagmus-associated lysosomal storage disease (LSD) genes were analyzed. RESULTS: A novel heterozygous mutation (c.2013G>A; p.R638H) of MANBA, which encodes lysosomal β-mannosidase, was identified in patients with autosomal-dominant nystagmus. An additional mutation (c.2346T>A; p.L749H) in MANBA was found by screening patients with sporadic nystagmus. MANBA was expressed in the pretectal nucleus of the developing midbrain, known to be involved in oculomotor and optokinetic nystagmus. Functional validation of these mutations demonstrated a significant decrease of β-mannosidase activities in the patients as well as in mutant-transfected HEK293T cells. Further analysis revealed that nystagmus is present in at least 24 different LSDs involving the brain. CONCLUSION: This is the first identification of MANBA mutations in patients with autosomal-dominant nystagmus, suggesting a new clinical entity. Because β-mannosidase activities are required for development of the oculomotor nervous system, our findings shed new light on the role of LSD-associated genes in the pathogenesis of infantile nystagmus.
PURPOSE: Genetic etiology of congenital/infantile nystagmus remains largely unknown. This study aimed to identify genomic mutations in patients with infantile nystagmus and an associated disease network. METHODS: Patients with inherited and sporadic infantile nystagmus were recruited for whole-exome and Sanger sequencing. β-Mannosidase activities were measured. Gene expression, protein-protein interaction, and nystagmus-associated lysosomal storage disease (LSD) genes were analyzed. RESULTS: A novel heterozygous mutation (c.2013G>A; p.R638H) of MANBA, which encodes lysosomal β-mannosidase, was identified in patients with autosomal-dominant nystagmus. An additional mutation (c.2346T>A; p.L749H) in MANBA was found by screening patients with sporadic nystagmus. MANBA was expressed in the pretectal nucleus of the developing midbrain, known to be involved in oculomotor and optokinetic nystagmus. Functional validation of these mutations demonstrated a significant decrease of β-mannosidase activities in the patients as well as in mutant-transfected HEK293T cells. Further analysis revealed that nystagmus is present in at least 24 different LSDs involving the brain. CONCLUSION: This is the first identification of MANBA mutations in patients with autosomal-dominant nystagmus, suggesting a new clinical entity. Because β-mannosidase activities are required for development of the oculomotor nervous system, our findings shed new light on the role of LSD-associated genes in the pathogenesis of infantile nystagmus.
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