Congenital muscular dystrophy type 1D (MDC1D) due to a large intragenic insertion/deletion, involving intron 10 of the LARGE gene

• Published in: European journal of human genetics : EJHG Vol. 19; no. 4; pp. 452 - 457
• Main Authors: CLARKE, Nigel F, MAUGENRE, Svetlana, ENDO, Tamao, CHOUERY, Eliane, CAMPBELL, Kevin P, MEGARBANE, André, GUICHENEY, Pascale, VANDEBROUCK, Aurélie, URTIZBEREA, J. Antoni, WILLER, Tobias, PEAT, Rachel A, GRAY, Prançoise, BOUCHET, Céline, MANYA, Hiroshi, VUILLAUMIER-BARROT, Sandrine
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01-04-2011
• Subjects: Base Sequence; Biological and medical sciences; Biopsy; Child; Child, Preschool; Chromosome Duplication - genetics; Codon, Nonsense; Diseases of striated muscles. Neuromuscular diseases; Dystroglycans - deficiency; Exons; Female; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genetics of eukaryotes. Biological and molecular evolution; Humans; INDEL Mutation; Intellectual Disability - genetics; Introns - genetics; Mannosyltransferases - metabolism; Medical genetics; Medical sciences; Molecular and cellular biology; Muscular Dystrophies - genetics; N-Acetylglucosaminyltransferases - genetics; N-Acetylglucosaminyltransferases - metabolism; Neurology; RNA Splicing - genetics; Chromosomal aberration; Nervous system diseases; Neuromuscular diseases; Congenital; alpha-dystroglycan; Insertion; congenital muscular dystrophy 1D; Muscular dystrophy; Genetic disease; Cerebral disorder; Eye disease; DNA duplication; Gene; Intron; muscle-eye-brain disease; DNA; Central nervous system disease; Deletion; Abnormal chromosome; Genetics; Muscle; Chromosome duplication; Dystrophin
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/ejhg.2010.212

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.