Congenital Muscular Dystrophy type 1D (MDC1D) due to a large intragenic insertion/deletion involving intron 10 of the gene

Pascale Guicheney (1) , Nigel F Clarke (1) , Svetlana Maugenre (1) , Aurélie Vandebrouck (1) , J Andoni Urtizberea (1) , Tobias Willer (1) , Rachel Peat (1) , Françoise Gray (1) , Céline Bouchet (1) , Hiroshi Manya (1) , Sandrine Vuillaumier-Barrot (1) , Tamao Endo (1) , Eliane Chouery (1) , Kevin P. Campbell (1) , André Mégarbané (1)

1 Unité UMR_S956

The gene is the rarest of the six known genetic causes of α-dystroglycanopathy. We report a further family with MDC1D due to a complex genomic rearrangement that was not apparent on standard sequencing of . 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 locus but sequencing of coding regions was normal. Analysis of cDNA showed an abnormal sequence inserted between exons 10 and 11 in most transcripts, predicted to introduce a premature stop codon. The abnormal sequences mapped to a spliced EST (DA935254) of unknown function, normally located 100 kb centromeric of on chromosome 22q12.3. Quantitative PCR analysis of the EST and adjacent regions showed twice the normal copy number in patient genomic DNA, consistent with a large intra-chromosomal duplication inserted into intron 10 of in a homozygous state. This insertion was associated with deletion of a central region of intron 10 but the exact breakpoints 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, is uncertain. POMT and POMGnT enzyme activities were normal in patient lymphoblasts, suggesting that defects in LARGE do not affect initiation of O-mannosyl-glycans.

Mots clés: congenital muscular dystrophy 1D; alpha-dystroglycan; DNA duplication

Pascale Guicheney, Nigel F Clarke, Svetlana Maugenre, Aurélie Vandebrouck, J Andoni Urtizberea, et al.. Congenital Muscular Dystrophy type 1D (MDC1D) due to a large intragenic insertion/deletion involving intron 10 of the gene. European Journal of Human Genetics, 2011, ⟨10.1038/ejhg.2010.212⟩. ⟨hal-00609410⟩