Disease relevance of DM1

• Myotonic dystrophy type I (DM1), which is caused by a non-coding CTG-repeat expansion in the dystrophia myotonica-protein kinase (DMPK) gene, is an RNA-mediated disease [1].
• Aberrant splicing of several genes has been reported to contribute to some symptoms of DM1, but the cause of muscle weakness in DM1 and elevated Ca2+ concentrations in cultured DM muscle cells is unknown [2].
• Heterozygous loss of SIX5 in mice causes cataracts and cardiac conduction disease, and homozygous loss also leads to sterility and decreased testicular mass, reminiscent of DM1 in humans [3].
• Myotonic dystrophy (DM1) is an autosomal-dominant multisystem disease characterized by progressive skeletal muscle weakness, myotonia, cataracts, cardiac arrhythmias, mild mental retardation, and endocrinopathies [3].
• DM2 is a progressive muscle disorder, although less severe than DM1 [4].

Psychiatry related information on DM1

• Fifty-six patients with DM1 and 29 patients with DM2 were subjected to muscle strength assessment, and to a complete battery of neuropsychological tests [4].

High impact information on DM1

• Myotonic dystrophy type 1 (DM1) is a debilitating multisystemic disorder caused by a CTG repeat expansion in the DMPK gene [2].
• The fetal variants, ASI(-) of RyR1 which lacks residue 3481-3485, and SERCA1b which differs at the C-terminal were significantly increased in skeletal muscles from DM1 patients and the transgenic mouse model of DM1 (HSA(LR)) [2].
• We also find an immobile fraction of GFP-MBNL1 in DM1 fibroblasts and a similar rapid exchange in endogenous CUG RNA foci [1].
• BACKGROUND: Myotonic dystrophy type 1 (DM1; OMIM #160900) is an autosomal-dominant genetic disorder with multisystemic clinical features associated with a CTG expansion in the 3' untranslated region of the DMPK gene on chromosome 19q13 [5].
• The RNA-FISH method is designed to detect the distinctive DM1 cellular phenotype, characterized by the presence of nuclei with focal ribonuclear inclusions (foci) containing the DMPK expanded transcripts [5].

Biological context of DM1

• One form of myotonic dystrophy, dystrophia myotonica 1 (DM1), is caused by the expansion of a (CTG)(n) repeat within the dystrophia myotonica-protein kinase (DMPK) gene located in chromosome region 19q13 [6].
• In skeletal muscles, DM1 may involve a novel, RNA-dominant disease mechanism in which transcripts from the mutant DMPK allele accumulate in the nucleus and compromise the regulation of alternative splicing [7].
• 3. A long-PCR protocol to detect the DM1 expansion is rapid, sensitive, and accurate, but interpretative limitations can occur when the expansion size exceeds the PCR amplification range and in cases of somatic mosaicism [5].
• We analyzed 6 CVS from DM1-predicted pregnancies and 6 CVS from DM1-negative pregnancies [5].
• CONCLUSION: Nuclear foci, and therefore the DM1 mutation they are caused by, can be detected efficiently on interphase nuclei of trophoblast cells with RNA-FISH when the CTG expansion is >200 copies [5].

Anatomical context of DM1

• RESULTS: In 4 DM1-predicted fetuses with a CTG expansion >200 CTG, varying numbers of ribonuclear inclusions were clearly visible in all cells [5].
• METHODS: To overcome these problems, we used RNA fluorescence in situ hybridization (RNA-FISH) to study cultured cells derived from chorionic villus samples (CVS) with the DM1 mutation [5].
• Myotonic dystrophy type 1 (DM1) is a multisystem disorder that affects skeletal and smooth muscle as well as the eye, heart, endocrine system, and central nervous system [8].
• Muscle strength and test scores for frontal lobe functions worsened significantly over time (p<0.01), in both DM1 and DM2 [4].
• In myotonic dystrophy type 1 (DM1) the muscle fibers express RNA containing an expanded CUG repeat (CUG(exp)) [9].

Analytical, diagnostic and therapeutic context of DM1

• Examination of post-mortem DM1 tissue by fluorescence in situ hybridization indicates that the mutant DMPK mRNA, with its expanded CUG repeat in the 3'-untranslated region, is widely expressed in cortical and subcortical neurons [7].
• To correlate CTG expansion and protein expression, we studied muscle specimens from 16 adult DM1 patients using three anti-DMPK antibodies for immunoblotting [10].
• Conjugates of the anti-CanAg humanized monoclonal antibody huC242 with the microtubule-formation inhibitor DM1 (a maytansinoid), or with the DNA alkylator DC1 (a CC1065 analogue), have been evaluated for their ability to eradicate mixed cell populations formed from CanAg-positive and CanAg-negative cells in culture and in xenograft tumors in mice [11].

References