O-mannosylation is an important protein modification in eukaryotes that is initiated by an evolutionarily conserved family of protein
O
-mannosyltransferases. The first mammalian protein
O
-mannosyltransferase gene described was the human
POMT1
. Mutations in the
hPOMT1
gene are responsible for Walker–Warburg syndrome (WWS), a severe recessive congenital muscular dystrophy associated with defects in neuronal migration that produce complex brain and eye abnormalities. During embryogenesis, the murine
Pomt1
gene is prominently expressed in the neural tube, the developing eye, and the mesenchyme. These sites of expression correlate with those in which the main tissue alterations are observed in WWS patients. We have inactivated a
Pomt1
allele by gene targeting in embryonic stem cells and produced chimeras transmitting the defect allele to offspring. Although heterozygous mice were viable and fertile, the total absence of
Pomt1
–
/
–
pups in the progeny of heterozygous intercrosses indicated that this genotype is embryonic lethal. An analysis of the mutant phenotype revealed that homozygous
Pomt1
–
/
–
mice suffer developmental arrest around embryonic day (E) 7.5 and die between E7.5 and E9.5. The
Pomt1
–
/
–
embryos present defects in the formation of Reichert's membrane, the first basement membrane to form in the embryo. The failure of this membrane to form appears to be the result of abnormal glycosylation and maturation of dystroglycan that may impair recruitment of laminin, a structural component required for the formation of Reichert's membrane in rodents. The targeted disruption of
mPomt1
represents an example of an engineered deletion of a known glycosyltransferase involved in
O
-mannosyl glycan synthesis.
Walker–Warburg syndrome (WWS) is an autosomal recessive disorder characterized by congenital muscular dystrophy, brain malformations and structural abnormalities of the eye. We have studied two WWS patients born to non‐consanguineous parents, and in both cases, we identified mutations in the fukutin gene responsible for this syndrome. One of the patients carries a homozygous‐single nucleotide insertion that produces a frameshift, being this the first time that this insertion has been described in homozygosis and causing a WWS phenotype. The other patient carries two novel mutations, one being a point mutation that produces an amino acid substitution, while the other is a deletion in the 3′UTR that affects the polyadenylation signal of the fukutin gene. This deletion would probably result in the complete loss of the fukutin transcripts from this allele. This is the first time a mutation localized outside of the fukutin coding region has been identified as a cause of WWS.
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