Journal article
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 : EJHG, Vol.19(4), pp.452-457
04/2011
DOI: 10.1038/ejhg.2010.212
PMCID: PMC3060325
PMID: 21248746
Abstract
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.
Details
- Title: Subtitle
- Congenital muscular dystrophy type 1D (MDC1D) due to a large intragenic insertion/deletion, involving intron 10 of the LARGE gene
- Creators
- Nigel F Clarke - , ParisSvetlana Maugenre - , ParisAurélie Vandebrouck - , ParisJ Andoni Urtizberea - , HendayeTobias Willer - , Iowa City, IARachel A Peat - , ParisFrançoise Gray - , ParisCéline Bouchet - , ParisHiroshi Manya - , Itabashi-ku, TokyoSandrine Vuillaumier-Barrot - , ParisTamao Endo - , Itabashi-ku, TokyoEliane Chouery - , BeirutKevin P Campbell - , Iowa City, IAAndré Mégarbané - , BeirutPascale Guicheney - , Paris
- Resource Type
- Journal article
- Publication Details
- European journal of human genetics : EJHG, Vol.19(4), pp.452-457
- Publisher
- Nature Publishing Group
- DOI
- 10.1038/ejhg.2010.212
- PMID
- 21248746
- PMCID
- PMC3060325
- ISSN
- 1018-4813
- eISSN
- 1476-5438
- Alternative title
- MDC1D due to a large intragenic insertion/deletion
- Language
- English
- Date published
- 04/2011
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute
- Record Identifier
- 9984020991302771
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