DMPK (Myotonic dystrophy protein kinase) is a skeletal and cardiac muscle enzyme of 623 amino-acids and Mr of 85kDa (larger than predicted Mr of 69kDa). It may be divided into 4 major domains: N-terminal, catalytic (PK-A type cyclic-AMP-dependent), coiled coil and C-terminal. Myotonic dystrophy is caused by a trinucleotide repeat expansion in the 3'-UTR of DMPK mRNA. This same repeat also lies close to the 5'-UTR of a second gene, Six5, a member of the Six family of homeobox transcription factors. Although some features of myotonic dystrophy may be influenced by reduced DMPK levels (muscle wasting, cardiac conduction defects) or reduced Six5 levels (cataracts),most clinical features, including myotonia, appear to be caused by the accumulation of expanded repeat RNA in the nucleus. This repeat accumulation interferes with the normal activity of nuclear factors, such as MBNL or muscleblind.
Abbreviations: wb = western blot if = immunolocalization ip = immunoprecipitation hu = human mo = mouse xe = xenopus lævis ch = chick dm = drosophila fi = fish (raja clavata) CRX = cross-reacting proteins p = preparation m = mapping a = applications ¶ = Also available at Developmental Studies Hybridoma Bank, IOWA(http://dshb.biology.uiowa.edu/)
Six5, a member of the Six family of homeobox transcription factors, encoded by 3 exons A, B & C, the homeodomain and nuclear localization signal being in exon A. Alternative splicing of exon B would result in expression of exon C in a different reading frame, C2.
MBNL1,MBNL2 are members of the human muscleblind-like (MBNL) family of proteins which bind RNA and regulate alternative splicing. MBNL isoforms colocalise with expanded RNA repeats in myotonic dystrophy cells.
The mismatch repair protein, MSH3, together with MSH2, forms the MutSb heterodimer which recognizes and repairs base pair mismatches and larger insertion/deletion loops in DNA. MSH3 is a potential therapeutic target to prevent expansions in triplet repeat diseases, such as myotonic dystrophy, since its ablation can prevent somatic and intergenerational repeat expansions, while producing little, if any, increase in cancer-related mutation rates.