Novel POMGnT1 mutations cause muscle-eye-brain disease in Chinese patients
Muscle-eye-brain (MEB) disease is a congenital muscular dystrophy (CMD) phenotype characterized by hypotonia at birth, brain structural abnormalities and ocular malformations. To date, few MEB cases have been reported in China where clinical recognition and genetic confirmatory testing on a research basis are recent developments. Here, we report the clinical and molecular genetics of three MEB disease patients. The patients had different degrees of muscle, eye and brain symptoms, ranging from congenital hypotonia, early-onset severe myopia and mental retardation to mild weakness, independent walking and language problems. This confirmed the expanding phenotypic spectrum of MEB disease with varying degrees of hypotonia, myopia and cognitive impairment. Brain magnetic resonance imaging showed cerebellar cysts, hypoplasia and characteristic brainstem flattening and kinking. Four candidate genes (POMGnT1, FKRP, FKTN and POMT2) were screened, and six POMGnT1 mutations (four novel) were identified, including five missense and one splice site mutation. Pathogenicity of the two novel variants in one patient was confirmed by POMGnT1 enzyme activity assay, protein expression and subcellular localization of mutant POMGnT1 in HeLa cells. Transfected cells harboring this patient’s L440R mutant POMGnT1 showed POMGnT1 mislocalization to both the Golgi apparatus and endoplasmic reticulum. We have provided clinical, histological, enzymatic and genetic evidence of POMGnT1 involvement in three unrelated MEB disease patients in China. The identification of novel POMGnT1 mutations and an expanded phenotypic spectrum contributes to an improved understanding of POMGnT1 structure–function relationships, CMD pathophysiology and genotype–phenotype correlations, while underscoring the need to consider POMGnT1 in Chinese MEB disease patients.
KeywordsMuscle-eye-brain disease POMGnT1 mutation α-dystroglycanopathy Enzyme activity
Congenital muscular dystrophy
Dulbecco modified Eagle medium
Keyhole limpet hemocyanin
- MEB disease
Magnetic resonance imaging
Polymerase chain reaction
Protein-O-linked mannose beta1,2-N-acetylglucosaminyltransferase 1
The authors are grateful to all the patients and their families who have participated in this study. We thank Dr. Anne Rutkowski for her comments and criticisms on the manuscript. This work was supported by grants from the Beijing Natural Science Foundation of China (7112133), the National Basic Research Program of China (973 Program, 2012CB944602), the National Natural Science Foundation of China (81271400), the Intramural Research Grant (23–5) for Neurological and Psychiatric Disorders of NCNP, a Comprehensive Research on Disability Health and Welfare from the Ministry of Health (H22-021), and the Research Foundation for Pharmaceutical Sciences.
Conflict of interest
The authors report no conflicts of interest.
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