Fairbrother, Una Louise; (1995) DMDL, an autosomal homologue of X-linked dystrophin; gene expression and cDNA cloning. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The Duchenne Muscular Dystrophy Like gene (DMDL (UTRN)) is an autosomal homologue of the X-linked Duchenne Muscular Dystrophy gene (DMD) which encodes dystrophin. DMDL (UTRN) maps to human chromosome 6q24 and mouse chromosome 10. The pattern of the DMDL (UTRN) gene expression in human and mouse was investigated by slot-blot and PCR analyses using RNA from a wide range of foetal and adult tissues. These studies have shown, in contrast to dystrophin which is expressed primarily in skeletal and cardiac muscle, DMDL (UTRN) is ubiquitously expressed, with relatively higher levels of expression in foetal than mature adult tissues. This thesis describes the cloning of 5.2Kb of the DMDL (UTRN) cDNA (full length 13Kb). Two unamplified cDNA libraries have been prepared from human placental mRNA and twelve independent overlapping cDNAs have been isolated. Insert DNA varied in length from 2Kb to 3.2Kb and in total spanned 5.2Kb. The cDNAs have been restriction mapped and sequenced and the nature of an unstable region discussed with reference to the nucleotide sequence of the DMDL (UTRN) gene. The amino acid sequence for human DMDL (UTRN) protein, utrophin, has been deduced and the protein structure compared with that of dystrophin to which it shows considerable amino acid sequence and structural homology. The homology between the two proteins rises towards a highly conserved cysteine rich region but declines towards the 5' end of the protein, mirroring the pattern of the nucleic acid homology. Since utrophin has a similar structure to dystrophin, it may perform a similar function in the cell. A restriction enzyme map of DMDL (UTRN) was generated from Southern blot analysis of Hindlll/Pvull digested genomic DNA. Using this information, the total genomic region spanned by cDNA inserts isolated in this study was estimated to be in excess of 58Kb and comprise at least 9 exons. The DMDL (UTRN) locus is inferred to be large but not as large as the DMD locus.

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