Protein O-mannosyltransferase activities in lymphoblasts from patients with alpha-dystroglycanopathies.

Abstract

Defects in O-mannosylation of alpha-dystroglycan cause some forms of congenital muscular dystrophy (CMD), the so-called alpha-dystroglycanopathies. Six genes are responsible for these diseases with overlapping phenotypes. We investigated the usefulness of a biochemical approach for the diagnosis and investigation of the alpha-dystroglycanopathies using immortalized lymphoblasts prepared from genetically diagnosed and undiagnosed CMD patients and from control subjects. We measured the activities of protein O-mannose beta1,2-N-acetylglucosaminyltransferase 1 (POMGnT1) and protein O-mannosyltransferase (POMT). Lymphoblasts from patients harbouring known mutations in either POMGNT1 or POMT1 showed a marked decrease in POMGnT1 or POMT activity, respectively, compared to controls. Furthermore, we identified pathogenic mutations in POMGNT1, POMT1 or POMT2 in six previously genetically uncharacterised patients who had very low enzyme activity. In conclusion, the lymphoblast-based enzymatic assay is a sensitive and useful method (i) to select patients harbouring POMGNT1, POMT1 or POMT2 mutations; (ii) to assess the pathogenicity of new or already described mutations.

• Authors: Hiroshi Manya, Céline Bouchet, Akiko Yanagisawa, Sandrine Vuillaumier-Barrot, Susana Quijano-Roy, Yasushi Suzuki, Svetlana Maugenre, Pascale Richard, Toshiyuki Inazu, Luciano Merlini, Norma B Romero, France Leturcq, Isabelle Bezier, Haluk Topaloglu, Brigitte Estournet, Nathalie Seta, Tamao Endo, Pascale Guicheney
• Journal: Neuromuscular disorders : NMD (Neuromuscul Disord) Vol. 18 Issue 1 Pg. 45-51 (Jan 2008) ISSN: 0960-8966 [Print] England
• PMID: 17869517 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DAG1 protein, human
• Genetic Markers
• Isoenzymes
• Dystroglycans
• Mannosyltransferases
• N-Acetylglucosaminyltransferases
• protein O-mannose beta-1,2-N-acetylglucosaminyltransferase
• protein O-mannosyltransferase

Topics

• Biological Assay (methods)
• Cell Line, Transformed
• Cells, Cultured
• DNA Mutational Analysis
• Down-Regulation (genetics)
• Dystroglycans (genetics)
• Enzyme Activation (genetics)
• Gene Expression Regulation, Enzymologic (genetics)
• Genetic Markers (genetics)
• Genetic Testing
• Hematopoietic Stem Cells (enzymology)
• Humans
• Isoenzymes (genetics, metabolism)
• Lymphocytes (enzymology)
• Mannosyltransferases (genetics)
• Muscular Dystrophies (diagnosis, enzymology, genetics)
• Mutation (genetics)
• N-Acetylglucosaminyltransferases (genetics)
• Predictive Value of Tests