Myotonic dystrophy type 1 (DM1) is a complex neuromuscular disease characterized by skeletal muscle wasting, weakness, and myotonia. DM1 is caused by the accumulation of CUG repeats, which alter the biological activities of RNA-binding proteins, including CUG-binding protein 1 (CUGBP1). CUGBP1 is an important skeletal muscle translational regulator that is activated by cyclin D3-dependent kinase 4 (CDK4). Here we show that mutant CUG repeats suppress Cdk4 signaling by increasing the stability and activity of glycogen synthase kinase 3β (GSK3β). Using a mouse model of DM1 (HSA LR ), we found that CUG repeats in the 3′ untranslated region (UTR) of human skeletal actin increase active GSK3β in skeletal muscle of mice, prior to the development of skeletal muscle weakness. Inhibition of GSK3β in both DM1 cell culture and mouse models corrected cyclin D3 levels and reduced muscle weakness and myotonia in DM1 mice. Our data predict that compounds normalizing GSK3β activity might be beneficial for improvement of muscle function in patients with DM1. IntroductionMyotonic dystrophy type 1 (DM1) is a complex disease affecting primarily skeletal muscle, causing myotonia, skeletal muscle weakness, and wasting (1). DM1 is caused by the expansion of polymorphic, noncoding CTG repeats in the 3′ untranslated region (UTR) of the dystrophia myotonica protein kinase (DMPK) gene (2, 3). The severity of DM1 correlates with the length of CTG expansions. The longest CTG expansions are observed in patients with a congenital form of DM1 that affects newborn children (1). Congenital DM1 is characterized by a delay in skeletal muscle development, leading to extreme muscle weakness and a weak respiratory system, which has been associated with a high mortality rate (4, 5). Expanded CTG repeats cause the disease through RNA CUG repeats that misregulate several CUG RNA-binding proteins, including CUGBP1 (CUGBP Elav-like family member 1, CELF1) and muscleblind 1 (MBNL1) (6-24). The mutant CUG aggregates sequester MBNL1, reducing splicing of MBNL1-regulated mRNAs (11,12,17). A portion of the mutant CUG repeats bind to CUGBP1 and elevate CUGBP1 protein levels through an increase in its stability (14). Phosphorylation of CUGBP1 by PKC also contributes to the increase in CUGBP1 stability (24).CUGBP1 is a highly conserved, multifunctional protein that regulates RNA processing on several levels, including translation, RNA stability, and splicing (9, 14-16, 18, 20-22, 25-32). The increase in CUGBP1 to the levels observed in the congenital DM1 leads to the delay of myogenesis in the CUGBP1 transgenic mouse model (18). Multiple functions of CUGBP1 are tightly regulated by phosphorylation at distinct sites (21,22,24). Phosphorylation of CUGBP1 by AKT at S28 controls nucleus-cytoplasm distribution of CUGBP1 and increases CUGBP1 affinity toward certain mRNA targets (21,22). Translational activity of CUGBP1 is regulated by cyclin D3/CDK4 phosphorylation at S302 (21,22,29,32).

Here we demonstrate biallelic mutations in sorbitol dehydrogenase (SORD) as the most frequent recessive form of hereditary neuropathies. We identified 45 cases from 38 families across multiple ethnicities, carrying a particular nonsense mutation in SORD, c.753delG; p.Ala253GlnfsTer27, either in homozygous or compound heterozygous state with a second variant. With an allele frequency of 0.004 in healthy controls, the p.Ala253GlnfsTer27 variant represents one of the most common pathogenic alleles in humans. SORD is an enzyme that converts sorbitol into fructose, in the two-step polyol pathway that has been implicated in diabetic neuropathy. In patient-derived fibroblasts, we find a complete loss of SORD protein as well as increased intracellular sorbitol. Also, serum fasting sorbitol level was over 100 times higher in patients homozygous for the p.Ala253GlnfsTer27 mutation compared to healthy individuals. In Drosophila, we show that loss of SORD orthologues causes synaptic degeneration and progressive motor impairment. Reducing the polyol influx by treatment with aldose reductase inhibitors normalized intracellular sorbitol levels in patient fibroblasts and in Drosophila, and also dramatically ameliorated motor and eye phenotypes. Together, these findings establish a potentially treatable cause in a significant fraction of patients with inherited neuropathies and may contribute to a better understanding of the pathophysiology of diabetic neuropathy.

Leukoencephalopathies are a diverse group of white matter disorders that can be difficult to diagnose. Using focused and whole-exome sequencing, Lynch et al. expand the known clinical and mutational spectrum of genetic leukoencephalopathy in adulthood, and describe the frequency and clinical and radiological phenotype of the most commonly mutated genes.

Myotonic dystrophy type 1 (DM1) lacks non-invasive and easy to measure biomarkers, still largely relying on semi-quantitative tests for diagnostic and prognostic purposes. Muscle biopsies provide valuable data, but their use is limited by their invasiveness. microRNA (miRNAs) are small non-coding RNAs regulating gene expression that are also present in biological fluids and may serve as diseases biomarkers. Thus, we tested plasma miRNAs in the blood of 36 DM1 patients and 36 controls. First, a wide miRNA panel was profiled in a patient subset, followed by validation using all recruited subjects. We identified a signature of nine deregulated miRNAs in DM1 patients: eight miRNAs were increased (miR-133a, miR-193b, miR-191, miR-140-3p, miR-454, miR-574, miR-885-5p, miR-886-3p) and one (miR-27b) was decreased. Next, the levels of these miRNAs were used to calculate a "DM1-miRNAs score". We found that both miR-133a levels and DM1-miRNAs score discriminated DM1 from controls significantly and Receiver-Operator Characteristic curves displayed an area under the curve of 0.94 and 0.97, respectively. Interestingly, both miR-133a levels and DM1-miRNAs score displayed an inverse correlation with skeletal muscle strength and displayed higher values in more compromised patients. In conclusion, we identified a characteristic plasma miRNA signature of DM1. Although preliminary, this study indicates miRNAs as potential DM1 humoral biomarkers.