Lysosomal storage disease in the brain: mutations of the β-mannosidase gene identified in autosomal dominant nystagmus.
OBJECTIVE
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.


CONCLUSIONS
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.
The Institute of Genomic Medicine, Wenzhou Medical University, Zhejiang, China.
Ping
P
Yu
Department of Ophthalmology, Heping Hospital, Changzhi Medical College, Shanxi, China.
Yun
Y
Cui
Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China.
Wanshi
W
Cai
The Institute of Genomic Medicine, Wenzhou Medical University, Zhejiang, China.
Honghu
H
Wu
The Institute of Genomic Medicine, Wenzhou Medical University, Zhejiang, China.
Xiaoqiang
X
Xiao
The Institute of Genomic Medicine, Wenzhou Medical University, Zhejiang, China.
Qianzhi
Q
Shao
Department of Ophthalmology, Heping Hospital, Changzhi Medical College, Shanxi, China.
Liang
L
Ma
The Institute of Genomic Medicine, Wenzhou Medical University, Zhejiang, China.
Sen
S
Guo
The Institute of Genomic Medicine, Wenzhou Medical University, Zhejiang, China.
Nana
N
Wu
State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Wenzhou, Zhejiang, China.
Zi-Bing
ZB
Jin
Department of Ophthalmology, Heping Hospital, Changzhi Medical College, Shanxi, China.
Yongjin
Y
Wang
Experimental Medicine Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA.
Tao
T
Cai
The Institute of Genomic Medicine, Wenzhou Medical University, Zhejiang, China.|Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China.
Zhong Sheng
ZS
Sun
State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Wenzhou, Zhejiang, China.
Jia
J
Qu
D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D016464:Lysosomal Storage Diseases / Q000235:genetics; D009154:Mutation; D020417:Nystagmus, Congenital / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D044902:beta-Mannosidase / Q000235:genetics*
D044902:beta-Mannosidase