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.