Publication
Title
Promoter alteration causes transcriptional repression of the POMGNT1 gene in limb-girdle muscular dystrophy type 2O
Author
Abstract
Limb-girdle muscular dystrophy type 2O (LGMD2O) belongs to a group of rare muscular dystrophies named dystroglycanopathies, which are characterized molecularly by hypoglycosylation of alpha-dystroglycan (alpha-DG). Here, we describe the first dystroglycanopathy patient carrying an alteration in the promoter region of the POMGNT1 gene (protein O-mannose beta-1,2-N-acetylglucosaminyltransferase 1), which involves a homozygous 9-bp duplication (-83_-75dup). Analysis of the downstream effects of this mutation revealed a decrease in the expression of POMGNT1 mRNA and protein because of negative regulation of the POMGNT1 promoter by the transcription factor ZNF202 (zinc-finger protein 202). By functional analysis of various luciferase constructs, we localized a proximal POMGNT1 promoter and we found a 75% decrease in luciferase activity in the mutant construct when compared with the wild type. Electrophoretic mobility shift assay (EMSA) revealed binding sites for the Sp1, Ets1 and GATA transcription factors. Surprisingly, the mutation generated an additional ZNF202 binding site and this transcriptional repressor bound strongly to the mutant promoter while failing to recognize the wild-type promoter. Although the genetic causes of dystroglycanopathies are highly variable, they account for only 50% of the cases described. Our results emphasize the importance of extending the mutational screening outside the gene-coding region in dystroglycanopathy patients of unknown aetiology, because mutations in noncoding regions may be the cause of disease. Our findings also underline the requirement to perform functional studies that may assist the interpretation of the pathogenic potential of promoter alterations. European Journal of Human Genetics (2012) 20, 945-952; doi:10.1038/ejhg.2012.40; published online 14 March 2012
Language
English
Source (journal)
European journal of human genetics / European Society of Human Genetics. - Leiden
Publication
Leiden : 2012
ISSN
1018-4813
Volume/pages
20:9(2012), p. 945-952
ISI
000307633700007
Full text (Publisher's DOI)
UAntwerpen
Faculty/Department
Research group
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identification
Creation 09.10.2012
Last edited 24.06.2017
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