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: S Saredi, A Ardissone, A Ruggieri, E Mottarelli, L Farina, R Rinaldi, E Silvestri, C Gandioli, S D'Arrigo, F Salerno, L Morandi, P Grammatico, C Pantaleoni, I Moroni, M Mora
• Journal: Journal of the neurological sciences (J Neurol Sci) Vol. 318 Issue 1-2 Pg. 45-50 (Jul 15 2012) ISSN: 1878-5883 [Electronic] Netherlands
• PMID: 22554691 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier B.V. All rights reserved.

Chemical References

• N-Acetylglucosaminyltransferases
• protein O-mannose beta-1,2-N-acetylglucosaminyltransferase

Topics

• Adolescent
• Child
• Child, Preschool
• Fatal Outcome
• Female
• Fetal Diseases (diagnosis, enzymology, genetics)
• Gene Rearrangement (genetics)
• Genetic Predisposition to Disease (genetics)
• Humans
• Male
• N-Acetylglucosaminyltransferases (genetics, metabolism)
• Phenotype
• Point Mutation (genetics)
• Pregnancy
• Severity of Illness Index
• Walker-Warburg Syndrome (diagnosis, enzymology, genetics)