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


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.


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



Creatine kinase


Congenital muscular dystrophy


Dulbecco modified Eagle medium




Endoplasmic reticulum


Fukutin-related protein






Horseradish peroxidase


Keyhole limpet hemocyanin

MEB disease

Muscle-eye-brain disease


Magnetic resonance imaging


Polymerase chain reaction


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


Protein-O-mannosyl transferase


Reverse transcription


Untranslated region



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.


  1. Balci B, Morris-Rosendahl DJ, Celebi A, Talim B, Topaloglu H, Dincer P (2007) Prenatal diagnosis of muscle-eye-brain disease. Prenat Diagn 27:51–54PubMedCrossRefGoogle Scholar
  2. Biancheri R, Bertini E, Falace A, Pedemonte M, Rossi A, D’Amico A, Scapolan S, Berqamino L, Petrini S, Cassandrini D, Broda P, Manfredi M, Zara F, Santorelli FM, Minetti C, Bruno C (2006) POMGnT1 mutations in congenital muscular dystrophy: genotype-phenotype correlation and expanded clinical spectrum. Arch Neurol 63:1491–1495PubMedCrossRefGoogle Scholar
  3. Demir E, Gucuyener K, Akturk A, Talim B, Konus O, Del Bo R, Ghezzi S, Comi GP (2009) An unusual presentation of muscle-eye-brain disease: severe eye abnormalities with mild muscle and brain involvement. Neuromuscul Disord 19:692–695PubMedCrossRefGoogle Scholar
  4. Diesen C, Saarinen A, Pihko H, Rosenlew C, Cormand B, Dobyns WB, Dieguez J, Valanne L, Joensuu T, Lehesjoki AE (2004) POMGnT1 mutation and phenotypic spectrum in muscle-eye-brain disease. J Med Genet 41:e115PubMedCrossRefGoogle Scholar
  5. Godfrey C, Clement E, Mein R, Brockington M, Smith J, Talim B, Straub V, Robb S, Quinlivan R, Feng L, Jimenez-Mallebrera C, Mercuri E, Manzur AY, Kinali M, Torelli S, Brown SC, Sewry CA, Bushby K, Topaloglu H, North K, Abbs S, Muntoni F (2007) Refining genotype phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan. Brain 130:2725–2735PubMedCrossRefGoogle Scholar
  6. Godfrey C, Foley AR, Clement E, Muntoni F (2011) Dystroglycanopathies: coming into focus. Opin Genet Dev 21:278–285CrossRefGoogle Scholar
  7. Hehr U, Uyanik G, Gross C, Walter MC, Bohring A, Cohen M, Oehl-Jaschkowitz B, Bird LM, Shamdeen GM, Bogdahn U, Schuierer G, Topaloglu H, Aigner L, Lochmuller H, Winkler J (2007) Novel POMGnT1 mutations define broader phenotypic spectrum of muscle-eye-brain disease. Neurogenetics 8:279–288PubMedCrossRefGoogle Scholar
  8. Hewitt JE (2009) Abnormal glycosylation of dystroglycan in human genetic disease. Biochim Biophys Acta 1792:853–861PubMedCrossRefGoogle Scholar
  9. Jiao H, Xiong H, Zhang YZ, Wang S, Yang YL, Wu XR (2011) Clinical and mutation analysis of a Chinese family with muscle eye brain disease. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 28:481–484PubMedGoogle Scholar
  10. Manya H, Sakai K, Kobayashi K, Taniguchi K, Kawakita M, Toda T, Endo T (2003) Loss-of-function of an N-acetylglucosaminyltransferase, POMGnT1, in muscle-eye-brain disease. Biochem Biophys Res Commun 306:93–97PubMedCrossRefGoogle Scholar
  11. Manya H, Bouchet C, Yanagisawa A, Vuillaumier-Barrot S, Quijano-Roy S, Suzuki Y, Maugenre S, Richard P, Inazu T, Merlini L, Romero NB, Leturcq F, Bezier I, Topaloglu H, Estournet B, Seta N, Endo T, Guicheney P (2008) Protein O-mannosyltransferase activities in lymphoblasts from patients with α-dystroglycanopathies. Neuromuscul Disord 18:45–51PubMedCrossRefGoogle Scholar
  12. Mercuri E, Messina S, Bruno C, Mora M, Pegoraro E, Comi GP, D’Amico A, Aiello C, Biancheri R, Berardinelli A, Boffi P, Cassandrini D, Laverda A, Moggio M, Morandi L, Moroni I, Pane M, Pezzani R, Pichiecchio A, Pini A, Minetti C, Mongini T, Mottarelli E, Ricci E, Ruggieri A, Saredi S, Scuderi C, Tessa A, Toscano A, Tortorella G, Trevisan CP, Uggetti C, Vasco G, Santorelli FM, Bertini E (2009) Congenital muscular dystrophies with defective glycosylation of dystroglycan: a population study. Neurology 72:1802–1809PubMedCrossRefGoogle Scholar
  13. Muntoni F, Voit T (2004) The congenital muscular dystrophies in 2004: a century of exciting progress. Neuromuscul Disord 14:635–649PubMedCrossRefGoogle Scholar
  14. Muntoni F, Torelli S, Wells DJ, Brown SC (2011) Muscular dystrophies due to glycosylation defects: diagnosis and therapeutic strategies. Curr Opin Neurol 24:437–442PubMedCrossRefGoogle Scholar
  15. Tachikawa M, Kanagawa M, Yu CC, Kobayashi K, Toda T (2012) Mislocalization of fukutin protein by disease-causing missense mutations can be rescued with treatments directed at folding amelioration. J Biol Chem 287:8398–8406PubMedCrossRefGoogle Scholar
  16. Taniguchi K, Kobayashi K, Saito K, Yamanouchi H, Ohnuma A, Hayashi YK, Manya H, Jin DK, Lee M, Parano E, Falsaperla R, Pavone P, Van Coster R, Talim B, Steinbrecher A, Straub V, Nishino I, Topaloglu H, Voit T, Endo T, Toda T (2003) Worldwide distribution and broader clinical spectrum of muscle-eye-brain disease. Hum Mol Genet 12:527–534PubMedCrossRefGoogle Scholar
  17. Unligil UM, Zhou S, Yuwaraj S, Sarkar M, Schachter H, Rini JM (2000) X-ray crystal structure of rabbit N-acetylglucosaminyltransferase I: catalytic mechanism and a new protein superfamily. EMBO J 19:5269–5280PubMedCrossRefGoogle Scholar
  18. Voglmeir J, Kaloo S, Laurent N, Meloni MM, Bohlmann L, Wilson IB, Flitsch SL (2011) Biochemical correlation of activity of the alpha-dystroglycan-modifying glycosyltransferase POMGnT1 with mutations in muscle-eye-brain disease. Biochem J 436:447–455PubMedCrossRefGoogle Scholar
  19. Xiong H, Kobayashi K, Tachikawa M, Manya H, Takeda S, Chiyonobu T, Fujikake N, Wang F, Nishimoto A, Morris GE, Nagai Y, Kanagawa M, Endo T, Toda T (2006) Molecular interaction between fukutin and POMGnT1 in the glycosylation pathway of alpha-dystroglycan. Biochem Biophys Res Commun 350:935–941PubMedCrossRefGoogle Scholar
  20. Xiong H, Wang S, Kobayashi K, Jiang Y, Wang J, Chang X, Yuan Y, Liu J, Toda T, Fukuyama Y, Wu X (2009) Fukutin gene retrotransposal insertion in a non-Japanese Fukuyama congenital muscular dystrophy (FCMD) patient. Am J Med Genet A 149A:2403–2408PubMedCrossRefGoogle Scholar
  21. Yoshida A, Kobayashi K, Manya H, Taniguchi K, Kano H, Mizuno M, Inazu T, Mitsuhashi H, Takahashi S, Takeuchi M, Herrmann R, Straub V, Talim B, Voit T, Topaloglu H, Toda T, Endo T (2001) Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltransferase, POMGnT1. Dev Cell 1:717–724PubMedCrossRefGoogle Scholar
  22. Zhang W, Betel D, Schachter H (2002) Cloning and expression of a novel UDP-GlcNAc:alpha-D-mannoside beta1,2-N-acetylglucosaminyltransferase homologous to UDP-GlcNAc:alpha-3-D-mannoside beta1,2-N-acetylglucosaminyltransferase I. Biochem J 361:153–162PubMedCrossRefGoogle Scholar
  23. Zhang W, Vajsar J, Cao P, Breningstall G, Diesen C, Dobyns W, Herrmann R, Lehesjoki AE, Steinbrecher A, Talim B, Toda T, Topaloglu H, Voit T, Schachter H (2003) Enzymatic diagnostic test for muscle-eye-brain type congenital muscular dystrophy using commercially available reagents. Clin Biochem 36:339–344PubMedCrossRefGoogle Scholar
  24. Zhang H, Ding J, Wang F, Yang H (2008) Prenatal diagnosis and genetic counseling of a Chinese Alport syndrome kindred. Genet Test 12:1–7PubMedCrossRefGoogle Scholar

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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