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DMD (dystrophin)

(last modified February 01, 2004)


Contents




Introduction


Dystrophin was discovered by ... .


The dystrophin gene


The dystrophin gene maps to chromosome X (Xp21.2).

Exon Exon size (bp) Intron size (kb) 5' cDNA position Splice after Remarks
1         5'UTR / .. bp coding

Legend:
Exon: numbering of exons and intron/exon boundaries are according to ..., with the first base of the Met-codon counted as position 1 (see ...reference sequence). Exon size: size of exon indicated in basepairs. Intron size: size of intron indicated in kilobasepairs. 5' cDNA position: first base of the exon (according to cDNA sequence ...). Splice after: splicing occurs in between of two coding triplets (0), after the first (1) or the second (2) base of a triplet. Remarks: 5'UTR = 5' untranslated region, 3"UTR = 3' untranslated region.

genomic sequences


The dystrophin RNA


GenBank: NM_004006

The DMD gene produces a range of different mRNA-transcripts encoding various dystrophin isoforms, i.e. proteins of varying lengths containing different segments of the basic dystrophin sequence. The isoforms are encoded by a range of different mRNA's which are generated by three processes; (i) the use of different, unique and often tissue-specific promoters, (ii) alternative splicing, and (iii) the use of different polyA-addition signals.

Tennyson et al. (1995) used quantitative RT-PCR to estimate that transcription of the 2.3 Mb DMD-gene requires approximately 16 hours (at an average elongation rate of 2.4 kb/min). Transcripts were spliced at the 5' end before transcription was complete, which provided strong evidence for co-transcriptional splicing. The rate of transcript accumulation was reduced at the 3' end relative to the 5' end, probably due to premature termination of transcription complexes (Tennyson et al. [1995]).

When comparing the chicken and human cDNA sequences Lemaire et al. [1988] observed a striking evolutionary conservation of three segments of the 3' untranslated region (3'UTR, 85% homology over a total of 920 nucleotides). Including the sequences from an amphibian and a cartilaginous fish Greener et al. [2002] refined this observation to two highly conserved regions separated by a non-conserved 700-2,000 nucleotide spacer; 

RNA transcripts


The dystrophin protein


Dystrophin is a rod-shaped protein, measuring about 150 nm, consisting of 3684 amino acids with a calculated molecular weight of 427 kDa. Dystrophin is predominantly hydrophilic throughout its entire length and 31% of the amino-acids are charged (i.e. Arg, Asp, Glu, His and Lys). A "Chou and Fasman" prediction of secondary structure reveals a very high potential for an alpha-helical formation over the majority of the sequence. Dystrophin can be separated into four domains:

 

Domain sub domain amino acids exons
actin binding domain   14-240 2-8
       
       
       
       
central rod domain   253-3040 8-61
  hinge 1 253-327 (8)-9
  repeat 1 337-447 10-11
  repeat 2 448-556 12-14
  repeat 3 557-667 14-16
  hinge 2 668-717 17
  repeat 4 718-828 (17)-20
  repeat 5 829-934 20-21
  repeat 6 935-1045 22-23
  repeat 7 1046-1154 (23)-(26)
  repeat 8 1155-1263 26-27
  repeat 9 1264-1367 28-(30)
  repeat 10 1368-1463 30-32
  repeat 11 1464-1568 32-(34)
  repeat 12 1569-1676 34-35
  repeat 13 1677-1778 36-37
  repeat 14 1779-1874 38-(40)
  repeat 15 1875-1973 40-41
  interruption 1974-1991 42
  repeat 16 1992-2101 42-43
  repeat 17 2102-2208 44-45
  repeat 18 2209-2318 46-48
  repeat 19 2319-2423 48-50
  hinge 3 2424-2470 50-51
  repeat 20 2471-2577 51-53
  repeat 21 2578-2686 53-(55)
  repeat 22 2687-2802 55-(57)
  repeat 23 2803-2931 57-59
  repeat 24 2932-3040 59-(61)
  hinge 4 3041-3112 61-64
Cysteine-rich domain   3080-3360 63-69
  dystroglycan binding site 3080-3408 63-70
  WW domain 3056-3092 62-63
  EF-hand 1 3130-3157 65
  EF-hand 2 3178-3206 65-66
  ZZ domain 3307-3354 68-69
Carboxy-terminal domain   3361-3685 70-79
  alpha1-syntrophin binding site 3444-3494 73-74
  ▀1-syntrophin binding site 3495-3535 74-75
  (Leu)6-heptad repeat 3558-3593 75

Dp71 is phosphorylated in vitro by p34cdc2 protein kinase Milner 93, JBC 21:21901-21905 (consensus site in exon 78 -TPGK-). Exon 1 encodes the 5'-untranslated region and 11 amino acids.

the protein

Evolution

Function


Dystrophin and disease: DMD, BMD, XLDC


Sequence variants  -  DMD mutation databases


Table of primer sequences


DNA-primers

RNA-primers


Dystrophin sequences



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