RGD Reference Report - Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome. - Rat Genome Database

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

Authors: Beltran-Valero de Bernabe, D  Currier, S  Steinbrecher, A  Celli, J  Van Beusekom, E  Van der Zwaag, B  Kayserili, H  Merlini, L  Chitayat, D  Dobyns, WB  Cormand, B  Lehesjoki, AE  Cruces, J  Voit, T  Walsh, CA  Van Bokhoven, H  Brunner, HG 
Citation: Beltran-Valero de Bernabe D, etal., Am J Hum Genet 2002 Nov;71(5):1033-43.
RGD ID: 731235
Pubmed: PMID:12369018   (View Abstract at PubMed)
PMCID: PMC419999   (View Article at PubMed Central)
DOI: DOI:10.1086/342975   (Journal Full-text)

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 alpha-dystroglycan. The implication of O-mannosylation in MEB and WWS suggests new lines of study in understanding the molecular basis of neuronal migration.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Walker-Warburg syndrome  IAGP 731235DNA:nonsense mutations more ...RGD 
Walker-Warburg syndrome  ISOPOMT1 (Homo sapiens)731235; 731235DNA:nonsense mutations more ...RGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Lissencephaly  IAGP 731235DNA:nonsense mutations more ...RGD 
Objects Annotated

Genes (Rattus norvegicus)
Pomt1  (protein-O-mannosyltransferase 1)

Genes (Mus musculus)
Pomt1  (protein-O-mannosyltransferase 1)

Genes (Homo sapiens)
POMT1  (protein O-mannosyltransferase 1)


Additional Information