Congenital muscular dystrophy type 1D (MDC1D) due to a large intragenic insertion/deletion, involving intron 10 of the LARGE gene.
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.
Inserm, U956, Faculté de Médecine Pierre et Marie Curie, Paris, France.
Nigel F
NF
Clarke
Svetlana
S
Maugenre
Aurélie
A
Vandebrouck
J Andoni
JA
Urtizberea
Tobias
T
Willer
Rachel A
RA
Peat
Françoise
F
Gray
Céline
C
Bouchet
Hiroshi
H
Manya
Sandrine
S
Vuillaumier-Barrot
Tamao
T
Endo
Eliane
E
Chouery
Kevin P
KP
Campbell
André
A
Mégarbané
Pascale
P
Guicheney
D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D058674:Chromosome Duplication / Q000235:genetics; D018389:Codon, Nonsense; D049030:Dystroglycans / Q000172:deficiency*; D005091:Exons; D005260:Female; D006801:Humans; D054643:INDEL Mutation; D008607:Intellectual Disability / Q000235:genetics; D007438:Introns / Q000235:genetics*; D008364:Mannosyltransferases / Q000378:metabolism; D009136:Muscular Dystrophies / Q000235:genetics*; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics* / Q000378:metabolism; D012326:RNA Splicing / Q000235:genetics
D018389:Codon, Nonsense; D049030:Dystroglycans; C117674:LARGE1 protein, human; D008364:Mannosyltransferases; D017351:N-Acetylglucosaminyltransferases; C443106:protein O-mannose beta-1,2-N-acetylglucosaminyltransferase; C082696:protein O-mannosyltransferase
Cell. 1991 Sep 20;66(6):1121-31
1913804
Hum Mutat. 2008 Nov;29(11):E231-41
18752264
J Hered. 1976 May-Jun;67(3):135-8
939913
Genome Res. 2006 Jan;16(1):55-65
16344560
J Neuropathol Exp Neurol. 1995 Jul;54(4):601-6
7602333
Annu Rev Genomics Hum Genet. 2002;3:199-242
12142364
Nature. 2002 Jul 25;418(6896):417-22
12140558
Science. 2010 Jan 1;327(5961):88-92
20044576
Brain. 2007 Oct;130(Pt 10):2725-35
17878207
Biochem Biophys Res Commun. 2006 Dec 1;350(4):935-41
17034757
Nat Clin Pract Neurol. 2006 Apr;2(4):222-30
16932553
Neuromuscul Disord. 2008 Jan;18(1):45-51
17869517
Nat Genet. 1992 Dec;2(4):292-300
1303282
Neurology. 2009 May 26;72(21):1802-9
19299310
Hum Genet. 2007 Jul;121(6):685-90
17436019
Hum Mol Genet. 2003 Nov 1;12(21):2853-61
12966029
Mol Cell Neurosci. 2005 Oct;30(2):160-72
16111892
Nat Genet. 2001 Jun;28(2):151-4
11381262