New POMT2 mutations causing congenital muscular dystrophy: identification of a founder mutation.

Dystroglycanopathies are a group of congenital muscular dystrophies (CMDs) with autosomal recessive inheritance, often associated with CNS and ocular involvement. They are characterized by the abnormal glycosylation of alpha-dystroglycan, and caused by mutations in at least six genes encoding enzymes: FKTN, POMGNT1, POMT1, POMT2, FKRP, and LARGE. POMT2 mutations have recently been identified in Walker-Warburg syndrome and in a milder muscle-eye-brain disease-like form. We studied mentally retarded patients with CMD, analyzed POMT2 by sequencing the coding regions, and also performed a haplotype analysis in all patients and their family members carrying the new POMT2 mutation. We report three novel POMT2 mutations. One of these, p.Tyr666Cys, was homozygous in two unrelated patients and in a compound heterozygous state in others. All patients showed severe diffuse muscle weakness, microcephaly, severe mental retardation, and marked lordoscoliosis with hyperextended head. Elevated CK levels, cerebral cortical atrophy, and cerebellar vermis hypoplasia were constant findings. Mild cardiac abnormalities, focal white matter abnormalities, or partial corpus callosum hypoplasia were detected in single cases. Eye involvement was absent or mild. By genotype analysis, we defined a distinct 170kb haplotype encompassing POMT2 and shared by all the subjects harboring the mutation p.Tyr666Cys. Our results broaden the clinical spectrum associated with POMT2 mutations, which should be considered in patients with CMD associated with microcephaly, and severe mental retardation with or without ocular involvement.