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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Congenital muscular dystrophy type 1D (MDC1D) due to a large intragenic insertion/deletion, involving intron 10 of the LARGE gene
European Journal of Human Genetics, Volume 19, No. 4, Year 2011
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Description
Mutation of the LARGE gene is the rarest of the six known genetic causes of α-dystroglycanopathy. We report further a family with MDC1D due to a complex genomic rearrangement that was not apparent on standard sequencing of LARGE. Two sisters in a consanguineous family had moderate mental retardation and cerebellar malformations, together with dystrophic changes and markedly reduced α-dystroglycan glycosylation staining on muscle biopsy. There was homozygous linkage to the LARGE locus but sequencing of LARGE coding regions was normal. Analysis of LARGE cDNA showed an abnormal sequence inserted between exons 10 and 11, in most of the transcripts, predicted to introduce a premature stop codon. The abnormal sequence mapped to a spliced EST (DA935254) of unknown function, normally located at 100 kb centromeric of LARGE on chromosome 22q12.3. Quantitative PCR analysis of the EST and adjacent regions showed twice the normal copy number in patients genomic DNA samples, consistent with a large intra-chromosomal duplication inserted into intron 10 of LARGE in a homozygous state. This insertion was associated with deletion of a central region of intron 10, but the exact break points of the deletion/duplication were not found, suggesting that an even more complex rearrangement may have occurred. The exact function of LARGE, a golgi protein, remains uncertain. POMT and POMGnT enzyme activities were normal in patients lymphoblast cells, suggesting that defects in LARGE do not affect the initiation of O-mannosyl glycans. © 2011 Macmillan Publishers Limited All rights reserved.
Authors & Co-Authors
Clarke, Nigel F.
France, Paris
Inserm
France, Paris
Sorbonne Université
Maugenre, Svetlana
France, Paris
Inserm
France, Paris
Sorbonne Université
Vandebrouck, Aurélie
France, Paris
Inserm
France, Paris
Sorbonne Université
Urtizberea, Jean Andoni M.
France, Paris
Ap-hp Assistance Publique - Hopitaux de Paris
Willer, Tobias
United States, Iowa City
University of Iowa
Peat, Rachel A.
France, Paris
Inserm
France, Paris
Sorbonne Université
Gray, Franscoise Françoise
France, Paris
Ap-hp Assistance Publique - Hopitaux de Paris
Bouchet, Céline
France, Paris
Hôpital Bichat-claude-bernard Ap-hp
Manya, Hiroshi
Japan, Tokyo
Tokyo Metropolitan Institute of Gerontology
Vuillaumier-Barrot, Sandrine
France, Paris
Hôpital Bichat-claude-bernard Ap-hp
Endo, Tamao
Japan, Tokyo
Tokyo Metropolitan Institute of Gerontology
Chouery, Éliane
Lebanon, Beirut
Université Saint-joseph de Beyrouth
Campbell, Kevin P.
United States, Iowa City
University of Iowa
Megarbane, Andre
Lebanon, Beirut
Université Saint-joseph de Beyrouth
France, Paris
Institut Jérôme Lejeune
France, Paris
Inserm
Guicheney, Pascale
France, Paris
Inserm
France, Paris
Sorbonne Université
France, Paris
Unité de Recherche Sur Les Maladies Cardiovasculaires, le Métabolisme et la Nutrition
Statistics
Citations: 51
Authors: 15
Affiliations: 9
Identifiers
Doi:
10.1038/ejhg.2010.212
ISSN:
10184813
e-ISSN:
14765438
Research Areas
Cancer
Disability
Genetics And Genomics
Maternal And Child Health
Study Approach
Quantitative