![]() The CTG repeats in the mutant DMPK allele are highly unstable and undergo somatic and intergenerational expansions ( 15–17). DM1 is caused by a CTG repeat expansion in the 3' untranslated region (3' UTR) of the Dystrophia Myotonica Protein Kinase ( DMPK) gene ( 12–14). The MBNL paralogs are involved in the multisystemic disorder Myotonic Dystrophy Type 1 (DM1), the most common cause of adult-onset muscular dystrophy, clinically affecting 1:8500 individuals ( 8–11). While the phenomenon of paralog compensation has been widely observed, the underlying molecular mechanisms and roles in preventing or modifying disease severity remain poorly understood.Īn example of paralog compensation is found with the paralogs of the Muscleblind-Like (MBNL) family of RNA-binding proteins, key regulators of RNA processing, including alternative splicing, alternative polyadenylation, RNA stability, and RNA subcellular localization ( 6, 7). Loss of a single paralog thereby results in no or only minor phenotypic consequences, whereas loss of both paralogs leads to severe phenotypes and lethality ( 3, 5). This robustness can arise from redundant genes, such as paralogs, with overlapping functions and temporospatial expression that can compensate for gene loss ( 3–5). ![]() Genetic robustness is the ability of an organism to maintain its reproductive fitness despite harmful genetic perturbations ( 1–4). Together, this study uncovers the compensatory mechanism by which loss of MBNL1 upregulates its paralog MBNL2 and highlights a potential role of the compensatory mechanism in DM1. We further find that the compensatory mechanism is active in a mouse DM1 model. Loss of MBNL1 increases the inclusion of exon 9, resulting in an alternative C-terminus lacking the PEST domain and the increase of MBNL2. We show that the C-terminus lacking exon 9 contains a PEST domain which causes proteasomal degradation. We find that inclusion of Mbnl2 exon 6 increases the translocation of MBNL2 to the nucleus, while the inclusion of Mbnl2 exon 9 shifts the reading frame to an alternative C-terminus. Here, we show that loss of MBNL1 increases the inclusion of Mbnl2 exon 6 and exon 9. Loss of MBNL1 increases the levels of its paralog MBNL2 in tissues where Mbnl2 expression is low, allowing MBNL2 to functionally compensate for MBNL1 loss. An example of such compensation are the paralogs of the Muscleblind-Like (MBNL) family of RNA-binding proteins that are sequestered and lose their function in Myotonic Dystrophy Type 1 (DM1). Loss of gene function can be compensated by paralogs with redundant functions. ![]()
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