Mutations in FLNC cause two distinct types of myopathy. Disease associated with mutations in filamin C rod domain leading to expression of a toxic protein presents with progressive proximal muscle weakness and shows focal destructive lesions of polymorphous aggregates containing desmin, myotilin and other proteins in the affected myofibres; these features correspond to the profile of myofibrillar myopathy. The second variant associated with mutations in the actin-binding domain of filamin C is characterized by weakness of distal muscles and morphologically by non-specific myopathic features. A frameshift mutation in the filamin C rod domain causing haploinsufficiency was also found responsible for distal myopathy with some myofibrillar changes but no protein aggregation typical of myofibrillar myopathies. Controversial data accumulating in the literature require re-evaluation and comparative analysis of phenotypes associated with the position of the FLNC mutation and investigation of the underlying disease mechanisms. This is relevant and necessary for the refinement of diagnostic criteria and developing therapeutic approaches. We identified a p.W2710X mutation in families originating from ethnically diverse populations and re-evaluated a family with a p.V930_T933del mutation. Analysis of the expanded database allows us to refine clinical and myopathological characteristics of myofibrillar myopathy caused by mutations in the rod domain of filamin C. Biophysical and biochemical studies indicate that certain pathogenic mutations in FLNC cause protein misfolding, which triggers aggregation of the mutant filamin C protein and subsequently involves several other proteins. Immunofluorescence analyses using markers for the ubiquitin-proteasome system and autophagy reveal that the affected muscle fibres react to protein aggregate formation with a highly increased expression of chaperones and proteins involved in proteasomal protein degradation and autophagy. However, there is a noticeably diminished efficiency of both the ubiquitin-proteasome system and autophagy that impairs the muscle capacity to prevent the formation or mediate the degradation of aggregates. Transfection studies of cultured muscle cells imitate events observed in the patient's affected muscle and therefore provide a helpful model for testing future therapeutic strategies.

Objectives Recent genome-wide association studies (GWAS) have identified more than 40 common sequence variants associated with type 2 diabetes (T2D). However, the results are not always the same in populations with differing genetic backgrounds. We evaluated a hypothesis that a North Asian population living in a geographic area with unusually harsh environmental conditions developed unique genetic risks. Methods We performed a population-based association study with 21 single-nucleotide polymorphisms (SNPs) in 9 genes selected according to the results of GWAS conducted in other populations. The study participants included 393 full-heritage Mongolian individuals, 177 diagnosed with T2D and 216 matched controls. Genotyping was performed by TaqMan methodology. Results The strongest association was detected with SNPs located within the potassium-channel coding KCNQ1 (highest OR=1.92; P=3.4×10−5) and ABCC8 (OR=1.79; P=5×10−4) genes. Genetic variants identified as strongly influencing the risk of T2D in other populations such as those in KCNJ11 or TCF7L2 genes did not show statistically significant association in Mongolia. Conclusions The strongest T2D risk-associated SNPs in Mongolians are located within 2 of 3 tested potassium-channel coding genes; accumulated variations in these genes may be related to environmental exposure to extreme cold.