title: Novel POMGNT1 point mutations and intragenic rearrangements associated with muscle-eye-brain disease.
abstract: Congenital muscular dystrophies due to defects in genes encoding proteins involved in α-dystroglycan (α-DG) glycosylation are a heterogeneous group of muscle disorders variably associated with central nervous system and eye abnormalities. One of the more severe is muscle-eye-brain disease (MEB). Mutations in genes coding for proven or putative glycosyltransferases (POMT1, POMT2, POMGnT1, fukutin, FKRP, and LARGE), the DPM3 gene encoding a DOL-P-Man synthase subunit, and the DAG1 gene encoding α-dystroglycan, have been associated with altered α-DG glycosylation. We report new POMGnT1 mutations and evaluate protein expression in 3 patients and 2 foetuses with variably severe MEB features. We identify two new point mutations (c.643C>T, c.1863delC), one new intragenic rearrangement (deletion of exons 2-8), and a new intron retention (between exons 21 and 22) resulting from a known point mutation c.1895+1G>T. Our study provides further evidence that rearrangements of the POMGnT1 gene are relatively common. Importantly, if heterozygous, they can be missed on standard genomic DNA sequencing. POMGNT1 protein analysis in 3 patients showed that the severity of the phenotype does not correlate with protein expression. Cerebral MRI is important for identifying MEB and α-dystroglycanopathy phenotypes in children and foetuses, and hence for directing the genetic analysis.
authors.affiliation: Division of Neuromuscular Diseases and Neuroimmunology, Foundation Neurological Institute C. Besta, Milano, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Saredi
authors.forename: A
authors.initials: A
authors.lastname: Ardissone
authors.forename: A
authors.initials: A
authors.lastname: Ruggieri
authors.forename: E
authors.initials: E
authors.lastname: Mottarelli
authors.forename: L
authors.initials: L
authors.lastname: Farina
authors.forename: R
authors.initials: R
authors.lastname: Rinaldi
authors.forename: E
authors.initials: E
authors.lastname: Silvestri
authors.forename: C
authors.initials: C
authors.lastname: Gandioli
authors.forename: S
authors.initials: S
authors.lastname: D'Arrigo
authors.forename: F
authors.initials: F
authors.lastname: Salerno
authors.forename: L
authors.initials: L
authors.lastname: Morandi
authors.forename: P
authors.initials: P
authors.lastname: Grammatico
authors.forename: C
authors.initials: C
authors.lastname: Pantaleoni
authors.forename: I
authors.initials: I
authors.lastname: Moroni
authors.forename: M
authors.initials: M
authors.lastname: Mora
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D017809:Fatal Outcome; D005260:Female; D005315:Fetal Diseases / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics; D015321:Gene Rearrangement / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D017354:Point Mutation / Q000235:genetics; D011247:Pregnancy; D012720:Severity of Illness Index; D058494:Walker-Warburg Syndrome / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics*
chemical_list: D017351:N-Acetylglucosaminyltransferases; C443106:protein O-mannose beta-1,2-N-acetylglucosaminyltransferase