Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome

Daniel Beltrán Valero De Bernabé, Sophie Currier, Alice Steinbrecher, Jacopo Celli, Ellen Van Beusekom, Bert Van der Zwaag, Hülya Kayserili, Luciano Merlini, David Chitayat, William B. Dobyns, Bru Cormand, Ana Elina Lehesjoki, Jesús Cruces, Thomas Voit, Christopher A. Walsh, Hans Van Bokhoven, Han G. Brunner

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Walker-Warburg syndrome (WWS) is an autosomal recessive developmental disorder characterized by congenital muscular dystrophy and complex brain and eye abnormalities. A similar combination of symptoms is presented by two other human diseases, muscle-eye-brain disease (MEB) and Fukuyama congenital muscular dystrophy (FCMD). Although the genes underlying FCMD (Fukutin) and MEB (POMGnT1) have been cloned, loci for WWS have remained elusive. The protein products of POMGnT1 and Fukutin have both been implicated in protein glycosylation. To unravel the genetic basis of WWS, we first performed a genomewide linkage analysis in 10 consanguineous families with WWS. The results indicated the existence of at least three WWS loci. Subsequently, we adopted a candidate-gene approach in combination with homozygosity mapping in 15 consanguineous families with WWS. Candidate genes were selected on the basis of the role of the FCMD and MEB genes. Since POMGnT1 encodes an O-mannoside N-acetylglucosaminyltransferase, we analyzed the possible implication of O-mannosyl glycan synthesis in WWS. Analysis of the locus for O-mannosyltransferase 1 (POMT1) revealed homozygosity in 5 of 15 families. Sequencing of the POMT1 gene revealed mutations in 6 of the 30 unrelated patients with WWS. Of the five mutations identified, two are nonsense mutations, two are frameshift mutations, and one is a missense mutation. Immunohistochemical analysis of muscle from patients with POMT1 mutations corroborated the O-mannosylation defect, as judged by the absence of glycosylation of α-dystroglycan. The implication of O-mannosylation in MEB and WWS suggests new lines of study in understanding the molecular basis of neuronal migration.

Original languageEnglish (US)
Pages (from-to)1033-1043
Number of pages11
JournalAmerican Journal of Human Genetics
Issue number5
StatePublished - 2002
Externally publishedYes

Bibliographical note

Funding Information:
We thank Drs. Rudolf Puttinger, Yvonne Hilhorst, Christine de Die, Koen DeVriendt, and Ernie Bongers, for contribution of family material for this study; Dr. Henk ter Laak, for immunohistochemical analysis of α-dystroglycan; and Dr. Luis Alberto Pérez Jurado, for his previous work on the POMT1 gene. The genomewide linkage analysis of some of the families was performed at the Centre de Genotypage, Paris. This work was supported by grants from the Dutch Foundation for Scientific Research (NWO, 903-42-190), the Prinses Beatrix Fund (MAR00-117), and the KNAW–van Leersum Fund. T.V. and L.M. were supported by E.U. grant QLRT-1999-00870, and T.V. was also supported by the Deutsche Forschungs Gemeinschaft (Str498/3-1); C.A.W. was supported by the National Institutes of Health (RO1 NS 35129).


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