While CDM is clearly associated with long progenitor repeat expansions, recent evidence suggests that repeat length is not the only operative mechanism in differentiating this more severe form of DM1. Although the predictive value of CTG repeat tract length can be improved by including specific phenotypic and genotypic parameters (see A Tighter Relationship Between CTG Repeat Length and DM1 Phenotype), this ‘correction’ alone cannot explain CDM. By contrast, evidence is building that epigenetic variations around the DMPK locus are a putative determinant of CDM vs. DM1 phenotypes. Moreover, an epigenetic effect may play a role in the biased inheritance pattern of CMD (see Epigenetics Underlying the Parent of Origin Effect in CDM).
Drs. Stella Lanni and Christopher Pearson (Hospital for Sick Children and University of Toronto) have examined the molecular genetics evidence underlying CDM and published a synthesis and disease model in Neurobiology of Disease (Lanni and Pearson, 2019). This review offers a conceptual framework to build upon in understanding the molecular mechanisms that determine phenotypic severity in CDM and DM1.
Modulation of Disease Severity in CDM and DM1
Inherited DMPK CTG expanded repeat length is a correlate but not an absolute determinant of the phenotypic expression of DM1. Since genetic testing reflects current level of somatic expansion, evidence now points toward utilizing estimated progenitor allele measurements in studies of genotype-phenotype correlations (Overend et al., 2019). Focusing on repeat length alone poses a trap—Drs. Lanni and Pearson note the extensive literature establishing that CDM cannot be treated as an early-onset and more severe DM1, but has distinctive clinical features of its own.
The authors note the extreme parent-of-origin effect in CDM (88-91% maternal bias) that strongly contrasts with the roughly equal transmission in childhood/infantile-onset DM1 and the paternal transmission bias in juvenile, adult, and late-onset DM1. Paternal transmission of CMD rarely occurs, even in cases of transmission of very long CTG repeats. Maternal factors other than genetics have largely been excluded, as has maternal transmission of mitochondrial mutations that could influence phenotype. To date, the data suggest that hypermethylation of CpG islands at the CTCF1 site upstream of maternally-inherited DMPK repeat expansions contributes toward CDM severity and also explains its maternal inheritance bias (Barbé et al., 2017).
Altered Gene Expression and CDM
Literature supporting altered gene expression and DMPK transcript processing in CDM was reviewed by Dr. Lanni and Pearson—of note was the observation that DMPK transcript levels are elevated in CDM fetal muscles and muscle precursor cells. Consistent with the MBNL sequestration model of DM, the elevated expanded repeat transcript levels are associated with the most severe phenotypes. Moreover, abundance of the DMPK antisense transcript is decreased in hypermethylated CDM muscles; the reduced antisense transcript, in turn, may reduce abundance of a protective 21nt RNA. Collectively, these events support the notion that hypermethylation contributes to CDM severity. Any potential contribution of RAN translation products to CDM is currently unknown.
Molecular Modeling of CDM1
Taken together, Dr. Lanni and Pearson suggest that current evidence supports a CDM1 model whereby CTCF1 site hypermethylation disrupts CTCF protein binding--this, in turn, alters gene expression. The subsequent increased transcription of the DMPK sense strand and decreased transcription of both the antisense and the neighboring SIX5 then contribute toward the more severe mis-splicing and phenotypic severity that are characteristic of CDM. Altered SIX5 expression may explain the maternal bias of CDM, via its impact on spermatogenesis.
The authors acknowledge that there are more questions remaining, but the existence of an integrated and testable molecular genetics model is a vital step toward understanding the disease mechanisms of and developing targeted therapies for CDM.
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