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. 2005 May 13;42(12):907–912. doi: 10.1136/jmg.2005.031963

POMT2 mutations cause α-dystroglycan hypoglycosylation and Walker-Warburg syndrome

J van Reeuwijk 1, M Janssen 1, C van den Elzen 1, d Beltran-Valero 1, P Sabatelli 1, L Merlini 1, M Boon 1, H Scheffer 1, M Brockington 1, F Muntoni 1, M Huynen 1, A Verrips 1, C Walsh 1, P Barth 1, H Brunner 1, H van Bokhoven 1
PMCID: PMC1735967  PMID: 15894594

Abstract

Background: Walker-Warburg syndrome (WWS) is an autosomal recessive condition characterised by congenital muscular dystrophy, structural brain defects, and eye malformations. Typical brain abnormalities are hydrocephalus, lissencephaly, agenesis of the corpus callosum, fusion of the hemispheres, cerebellar hypoplasia, and neuronal overmigration, which causes a cobblestone cortex. Ocular abnormalities include cataract, microphthalmia, buphthalmos, and Peters anomaly. WWS patients show defective O-glycosylation of α-dystroglycan (α-DG), which plays a key role in bridging the cytoskeleton of muscle and CNS cells with extracellular matrix proteins, important for muscle integrity and neuronal migration. In 20% of the WWS patients, hypoglycosylation results from mutations in either the protein O-mannosyltransferase 1 (POMT1), fukutin, or fukutin related protein (FKRP) genes. The other genes for this highly heterogeneous disorder remain to be identified.

Objective: To look for mutations in POMT2 as a cause of WWS, as both POMT1 and POMT2 are required to achieve protein O-mannosyltransferase activity.

Methods: A candidate gene approach combined with homozygosity mapping.

Results: Homozygosity was found for the POMT2 locus at 14q24.3 in four of 11 consanguineous WWS families. Homozygous POMT2 mutations were present in two of these families as well as in one patient from another cohort of six WWS families. Immunohistochemistry in muscle showed severely reduced levels of glycosylated α-DG, which is consistent with the postulated role for POMT2 in the O-mannosylation pathway.

Conclusions: A fourth causative gene for WWS was uncovered. These genes account for approximately one third of the WWS cases. Several more genes are anticipated, which are likely to play a role in glycosylation of α-DG.

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Selected References

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  1. Beltrán-Valero de Bernabé Daniel, Currier Sophie, Steinbrecher Alice, Celli Jacopo, van Beusekom Ellen, van der Zwaag Bert, Kayserili Hülya, Merlini Luciano, Chitayat David, Dobyns William B. Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome. Am J Hum Genet. 2002 Oct 4;71(5):1033–1043. doi: 10.1086/342975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Cenni V., Sabatelli P., Mattioli E., Marmiroli S., Capanni C., Ognibene A., Squarzoni S., Maraldi N. M., Bonne G., Columbaro M. Lamin A N-terminal phosphorylation is associated with myoblast activation: impairment in Emery-Dreifuss muscular dystrophy. J Med Genet. 2005 Mar;42(3):214–220. doi: 10.1136/jmg.2004.026112. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cormand B., Pihko H., Bayés M., Valanne L., Santavuori P., Talim B., Gershoni-Baruch R., Ahmad A., van Bokhoven H., Brunner H. G. Clinical and genetic distinction between Walker-Warburg syndrome and muscle-eye-brain disease. Neurology. 2001 Apr 24;56(8):1059–1069. doi: 10.1212/wnl.56.8.1059. [DOI] [PubMed] [Google Scholar]
  4. Currier Sophie C., Lee Christine K., Chang Bernard S., Bodell Adria L., Pai G. Shashidhar, Job Leela, Lagae Lieven G., Al-Gazali Lihadh I., Eyaid Wafaa M., Enns Greg. Mutations in POMT1 are found in a minority of patients with Walker-Warburg syndrome. Am J Med Genet A. 2005 Feb 15;133A(1):53–57. doi: 10.1002/ajmg.a.30487. [DOI] [PubMed] [Google Scholar]
  5. Dalkilic Isin, Kunkel Louis M. Muscular dystrophies: genes to pathogenesis. Curr Opin Genet Dev. 2003 Jun;13(3):231–238. doi: 10.1016/s0959-437x(03)00048-0. [DOI] [PubMed] [Google Scholar]
  6. Dobyns W. B., Pagon R. A., Armstrong D., Curry C. J., Greenberg F., Grix A., Holmes L. B., Laxova R., Michels V. V., Robinow M. Diagnostic criteria for Walker-Warburg syndrome. Am J Med Genet. 1989 Feb;32(2):195–210. doi: 10.1002/ajmg.1320320213. [DOI] [PubMed] [Google Scholar]
  7. Endo T. O-mannosyl glycans in mammals. Biochim Biophys Acta. 1999 Dec 6;1473(1):237–246. doi: 10.1016/s0304-4165(99)00182-8. [DOI] [PubMed] [Google Scholar]
  8. Endo Tamao, Toda Tatsushi. Glycosylation in congenital muscular dystrophies. Biol Pharm Bull. 2003 Dec;26(12):1641–1647. doi: 10.1248/bpb.26.1641. [DOI] [PubMed] [Google Scholar]
  9. Ervasti J. M., Campbell K. P. Membrane organization of the dystrophin-glycoprotein complex. Cell. 1991 Sep 20;66(6):1121–1131. doi: 10.1016/0092-8674(91)90035-w. [DOI] [PubMed] [Google Scholar]
  10. Gentzsch M., Tanner W. The PMT gene family: protein O-glycosylation in Saccharomyces cerevisiae is vital. EMBO J. 1996 Nov 1;15(21):5752–5759. [PMC free article] [PubMed] [Google Scholar]
  11. Grewal Prabhjit K., Hewitt Jane E. Glycosylation defects: a new mechanism for muscular dystrophy? Hum Mol Genet. 2003 Aug 12;12(SPEC):R259–R264. doi: 10.1093/hmg/ddg272. [DOI] [PubMed] [Google Scholar]
  12. Herrmann R., Straub V., Blank M., Kutzick C., Franke N., Jacob E. N., Lenard H. G., Kröger S., Voit T. Dissociation of the dystroglycan complex in caveolin-3-deficient limb girdle muscular dystrophy. Hum Mol Genet. 2000 Sep 22;9(15):2335–2340. doi: 10.1093/oxfordjournals.hmg.a018926. [DOI] [PubMed] [Google Scholar]
  13. Ichimiya Tomomi, Manya Hiroshi, Ohmae Yoshiko, Yoshida Hideki, Takahashi Kuniaki, Ueda Ryu, Endo Tamao, Nishihara Shoko. The twisted abdomen phenotype of Drosophila POMT1 and POMT2 mutants coincides with their heterophilic protein O-mannosyltransferase activity. J Biol Chem. 2004 Jul 22;279(41):42638–42647. doi: 10.1074/jbc.M404900200. [DOI] [PubMed] [Google Scholar]
  14. Jiménez-Mallebrera Cecilia, Torelli Silvia, Brown Susan C., Feng Lucy, Brockington Martin, Sewry Caroline A., Beltrán-Valero De Bernabé Daniel, Muntoni Francesco. Profound skeletal muscle depletion of alpha-dystroglycan in Walker-Warburg syndrome. Eur J Paediatr Neurol. 2003;7(3):129–137. doi: 10.1016/s1090-3798(03)00042-4. [DOI] [PubMed] [Google Scholar]
  15. Kanagawa Motoi, Saito Fumiaki, Kunz Stefan, Yoshida-Moriguchi Takako, Barresi Rita, Kobayashi Yvonne M., Muschler John, Dumanski Jan P., Michele Daniel E., Oldstone Michael B. A. Molecular recognition by LARGE is essential for expression of functional dystroglycan. Cell. 2004 Jun 25;117(7):953–964. doi: 10.1016/j.cell.2004.06.003. [DOI] [PubMed] [Google Scholar]
  16. Kim D. S., Hayashi Y. K., Matsumoto H., Ogawa M., Noguchi S., Murakami N., Sakuta R., Mochizuki M., Michele D. E., Campbell K. P. POMT1 mutation results in defective glycosylation and loss of laminin-binding activity in alpha-DG. Neurology. 2004 Mar 23;62(6):1009–1011. doi: 10.1212/01.wnl.0000115386.28769.65. [DOI] [PubMed] [Google Scholar]
  17. Manya Hiroshi, Chiba Atsuro, Yoshida Aruto, Wang Xiaohui, Chiba Yasunori, Jigami Yoshifumi, Margolis Richard U., Endo Tamao. Demonstration of mammalian protein O-mannosyltransferase activity: coexpression of POMT1 and POMT2 required for enzymatic activity. Proc Natl Acad Sci U S A. 2003 Dec 29;101(2):500–505. doi: 10.1073/pnas.0307228101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Martin-Rendon Enca, Blake Derek J. Protein glycosylation in disease: new insights into the congenital muscular dystrophies. Trends Pharmacol Sci. 2003 Apr;24(4):178–183. doi: 10.1016/S0165-6147(03)00050-6. [DOI] [PubMed] [Google Scholar]
  19. Martín-Blanco E., García-Bellido A. Mutations in the rotated abdomen locus affect muscle development and reveal an intrinsic asymmetry in Drosophila. Proc Natl Acad Sci U S A. 1996 Jun 11;93(12):6048–6052. doi: 10.1073/pnas.93.12.6048. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Michele Daniel E., Barresi Rita, Kanagawa Motoi, Saito Fumiaki, Cohn Ronald D., Satz Jakob S., Dollar James, Nishino Ichizo, Kelley Richard I., Somer Hannu. Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies. Nature. 2002 Jul 25;418(6896):417–422. doi: 10.1038/nature00837. [DOI] [PubMed] [Google Scholar]
  21. Michele Daniel E., Campbell Kevin P. Dystrophin-glycoprotein complex: post-translational processing and dystroglycan function. J Biol Chem. 2003 Jan 29;278(18):15457–15460. doi: 10.1074/jbc.R200031200. [DOI] [PubMed] [Google Scholar]
  22. Moore Steven A., Saito Fumiaki, Chen Jianguo, Michele Daniel E., Henry Michael D., Messing Albee, Cohn Ronald D., Ross-Barta Susan E., Westra Steve, Williamson Roger A. Deletion of brain dystroglycan recapitulates aspects of congenital muscular dystrophy. Nature. 2002 Jul 25;418(6896):422–425. doi: 10.1038/nature00838. [DOI] [PubMed] [Google Scholar]
  23. Muntoni Francesco, Brockington Martin, Torelli Silvia, Brown Susan C. Defective glycosylation in congenital muscular dystrophies. Curr Opin Neurol. 2004 Apr;17(2):205–209. doi: 10.1097/00019052-200404000-00020. [DOI] [PubMed] [Google Scholar]
  24. Reese M. G., Eeckman F. H., Kulp D., Haussler D. Improved splice site detection in Genie. J Comput Biol. 1997 Fall;4(3):311–323. doi: 10.1089/cmb.1997.4.311. [DOI] [PubMed] [Google Scholar]
  25. Schachter Harry, Vajsar Jiri, Zhang Wenli. The role of defective glycosylation in congenital muscular dystrophy. Glycoconj J. 2004;20(5):291–300. doi: 10.1023/B:GLYC.0000033626.65127.e4. [DOI] [PubMed] [Google Scholar]
  26. Willer Tobias, Amselgruber Werner, Deutzmann Rainer, Strahl Sabine. Characterization of POMT2, a novel member of the PMT protein O-mannosyltransferase family specifically localized to the acrosome of mammalian spermatids. Glycobiology. 2002 Nov;12(11):771–783. doi: 10.1093/glycob/cwf086. [DOI] [PubMed] [Google Scholar]
  27. Willer Tobias, Valero M. Carmen, Tanner Widmar, Cruces Jesus, Strahl Sabine. O-mannosyl glycans: from yeast to novel associations with human disease. Curr Opin Struct Biol. 2003 Oct;13(5):621–630. doi: 10.1016/j.sbi.2003.09.003. [DOI] [PubMed] [Google Scholar]
  28. de Bernabé D. Beltrán-Valero, van Bokhoven H., van Beusekom E., Van den Akker W., Kant S., Dobyns W. B., Cormand B., Currier S., Hamel B., Talim B. A homozygous nonsense mutation in the fukutin gene causes a Walker-Warburg syndrome phenotype. J Med Genet. 2003 Nov;40(11):845–848. doi: 10.1136/jmg.40.11.845. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. van Reeuwijk J., Brunner H. G., van Bokhoven H. Glyc-O-genetics of Walker-Warburg syndrome. Clin Genet. 2005 Apr;67(4):281–289. doi: 10.1111/j.1399-0004.2004.00368.x. [DOI] [PubMed] [Google Scholar]

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