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5) Myotonic Dystrophy - DMPK, Six5, MBNL1 and 2, MSH3


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/)

Name

Clone

Type

Epitope (aa)

Applications

Species
ve (x-ve)

CRX
Cross-reacting proteins

References

DMPK 16 mAbs

MANDM16G8, 141G1catalytic aa R-IK---Iwbhu, rb, moMANY, inc MRCKa/b35, 36
MANDM210A7G1catalytic aa FDLV-DGwbhusome35, 36
MANDM38B5, 10(low)G1coilwbhu35, 36
MANDM49H9, 49G1catalytic aa FDLV-DGwbhu35, 36
MANDM55G12, 64G1catalyticwbhu35, 36
MANDM67E4B7, 99G1catalyticwbhu35, 36
MANDM712G5G1catalytic aa TPD-EG55Kd only on wbhu, rb55Kd skeletal muscle protein and others35, 36
MANDM87E7G1catalytic aa TPD-EG55Kd only on wbhu, rb55Kd skeletal muscle protein35, 36
MANDM93D10, 199G1coilwbhu35, 36
MANDM102H12, 199G1coilwbhu35, 36
MANDM116B6G1coilwbhusome35, 36
MANDM127E4G2G1coilwbhu35, 36
MANDM1312A4G1coilwbhu35, 36
MANDM147E6G1coilwbhusome35, 36
MANDM155C9G1coilwbhusome35, 36
MANDM169A4G1coilwbhu35, 36

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.


Name

Clone

Type

Epitope (aa)

Applications

Species
ve (x-ve)

CRX
Cross-reacting proteins

References

Six5 18 mAbs

MANSIX5A1 ¶2A6G1P80-R85wb, ifhu40
MANSIX5A2 ¶3B4G1S72-S78wb, ifhuca 140kD in lung40
MANSIX5A3 ¶3D9G1S9-A20wb, ifhu40
MANSIX5A4 ¶3E11G1S9-A20wb, ifhu40
MANSIX5A5 ¶10B12G1P80-R85wb, ifhu40
MANSIX5A6 ¶1C11G1S72-S78wb, ifhu40
MANSIX5A7 ¶3G10G1S9-A20wb, ifhu40
MANSIX5A8 ¶7G4G2aP80-R85wb, ifhu40
MANSIX5A9 ¶2G8G1S9-A20wb, ifhu40
MANSIX5A10 ¶4H7G1not mappedwb, ifhuca 85kD in lung40
MANSIX5A11 ¶2H1G1not mappedwb, ifhuca 200kD in lung40
MANSIX5A12 ¶4E7G1not mappedwb, ifhuca 120kD in lung40
MANSIX5B1 ¶6E10G1not mappedwb, ifhu40
MANSIX5B2 ¶10B3G1not mappedwb, ifhu40
MANSIX5B3 ¶10D2G1not mappedwb, ifhu40
MANSIX5B4 ¶ 9G10 G1 not mapped wb, if hu 40
MANSIX5C2a ¶6C1G2anot mappedWB RECOMB. ONLYhu40
MANSIX5C2b ¶3A1G3not mappedWB RECOMB. ONLYhu40

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.


Name

Clone

Type

Epitope (aa)

Applications

Species
ve (x-ve)

CRX
Cross-reacting proteins

References

MBNL1 2 mAbs and MBNL2 3mAbs

MB1a(4A8)4A8, 216G1linker between 2 Zn fingers aa VSPSLwb, ifhu, mo45
MB1b(5F9)5F9G1not mappedwbhu, mo52
MB2a(3B4)3B4, 358G2baa PYLAwbhu, mo52
MB2b(6A10)6A10G2baa PYLAwbhu52
MB2c(8B1)8B1G1not mappedwbhu52

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.


Name

Clone

Type

Epitope (aa)

Applications

Species
ve (x-ve)

CRX
Cross-reacting proteins

References

MSH3 4 mAbs

MSH3MAB11F6G1aa SLRSSASwb, if mo55
MSH3MAB22F11, 157G1aa SLRSSASwb, ifmo55
MSH3MAB35A5G1aa YTPLELQYwb, ifhu, mo55
MSH3MAB48E6G1aa YTPLELQYwb, ifhu, mo55