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Molecular Genetics and Genomics

, Volume 288, Issue 7–8, pp 297–308 | Cite as

Novel POMGnT1 mutations cause muscle-eye-brain disease in Chinese patients

  • Hui Jiao
  • Hiroshi Manya
  • Shuo Wang
  • Yanzhi Zhang
  • Xiaoqing Li
  • Jiangxi Xiao
  • Yanling Yang
  • Kazuhiro Kobayashi
  • Tatsushi Toda
  • Tamao Endo
  • Xiru Wu
  • Hui XiongEmail author
Original Paper

Abstract

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.

Keywords

Muscle-eye-brain disease POMGnT1 mutation α-dystroglycanopathy Enzyme activity 

Abbreviations

CK

Creatine kinase

CMD

Congenital muscular dystrophy

DMEM

Dulbecco modified Eagle medium

EMG

Electromyogram

ER

Endoplasmic reticulum

FKRP

Fukutin-related protein

FKTN

Fukutin

GlcNAc

N-acetylglucosamine

HRP

Horseradish peroxidase

KLH

Keyhole limpet hemocyanin

MEB disease

Muscle-eye-brain disease

MRI

Magnetic resonance imaging

PCR

Polymerase chain reaction

POMGnT1

Protein-O-linked mannose beta1,2-N-acetylglucosaminyltransferase 1

POMT

Protein-O-mannosyl transferase

RT

Reverse transcription

UTR

Untranslated region

Notes

Acknowledgments

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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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Hui Jiao
    • 1
  • Hiroshi Manya
    • 2
  • Shuo Wang
    • 1
  • Yanzhi Zhang
    • 1
  • Xiaoqing Li
    • 3
  • Jiangxi Xiao
    • 4
  • Yanling Yang
    • 1
  • Kazuhiro Kobayashi
    • 5
  • Tatsushi Toda
    • 5
  • Tamao Endo
    • 2
  • Xiru Wu
    • 1
  • Hui Xiong
    • 1
    Email author
  1. 1.Department of PediatricsPeking University First HospitalBeijingChina
  2. 2.Molecular Glycobiology, Research Team for Mechanism of AgingTokyo Metropolitan Geriatric Hospital and Institute of GerontologyTokyoJapan
  3. 3.Department of Child OphthalmologyPeking University First HospitalBeijingChina
  4. 4.Department of RadiologyPeking University First HospitalBeijingChina
  5. 5.Division of Neurology/Molecular Brain ScienceKobe University Graduate School of MedicineKobeJapan

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