BackgroundThousands of long non-coding RNA (lncRNA) genes are annotated in the human genome. Recent studies showed the key role of lncRNAs in a variety of fundamental cellular processes. Dysregulation of lncRNAs can drive tumorigenesis and they are now considered to be a promising therapeutic target in cancer. However, how lncRNAs contribute to the development of hereditary diseases in human is still mostly unknown.ResultsThis review is focused on hereditary diseases in the pathogenesis of which long non-coding RNAs play an important role.ConclusionsFundamental research in the field of molecular genetics of lncRNA is necessary for a more complete understanding of their significance. Future research will help translate this knowledge into clinical practice which will not only lead to an increase in the diagnostic rate but also in the future can help with the development of etiotropic treatments for hereditary diseases.

Mutations in DES, encoding desmin protein, are associated with different kinds of skeletal and/or cardiac myopathies. However, it is unknown, whether DES mutations are associated with left ventricular hypertrabeculation (LVHT). Here, we performed a clinical examination and subsequent genetic analysis in a family, with two individuals presenting LVHT with conduction disease and skeletal myopathy. The genetic analysis revealed a novel small in‐frame deletion within the DES gene, p.Q113_L115del, affecting the α‐helical rod domain. Immunohistochemistry analysis of explanted myocardial tissue from the index patient revealed an abnormal cytoplasmic accumulation of desmin and a degraded sarcomeric structure. Cell transfection experiments with wild‐type and mutant desmin verified the cytoplasmic aggregation and accumulation of mutant desmin. Cotransfection experiments were performed to model the heterozygous state of the patients and revealed a dominant negative effect of the mutant desmin on filament assembly. DES:p.Q113_L115del is classified as a pathogenic mutation associated with dilated cardiomyopathy with prominent LVHT.

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Recently, we and others identified de novo FBXO11 variants as causative for a variable neurodevelopmental disorder (NDD). We now assembled clinical and mutational information on 23 additional individuals. The phenotypic spectrum remains highly variable, with developmental delay and/or intellectual disability as the core feature and behavioral anomalies, hypotonia and various facial dysmorphism as frequent aspects. The mutational spectrum includes intragenic deletions, likely gene disrupting and missense variants distributed across the protein. To further characterize the functional consequences of FBXO11 missense variants, we analyzed their effects on protein expression and localization by overexpression of 17 different mutant constructs in HEK293 and HeLa cells. We found that the majority of missense variants resulted in subcellular mislocalization and/or reduced FBXO11 protein expression levels. For instance, variants located in the nuclear localization signal and the N-terminal F-Box domain lead to altered subcellular localization with exclusion from the nucleus or the formation of cytoplasmic aggregates and to reduced protein levels in western blot. In contrast, variants localized in the C-terminal Zn-finger UBR domain lead to an accumulation in the cytoplasm without alteration of protein levels. Together with the mutational data our functional results suggest that most missense variants likely lead to a loss of the original FBXO11 function and thereby highlight haploinsufficiency as the most likely disease mechanism for FBXO11-associated NDDs.

Background Stickler syndrome (STL) is a clinically variable and genetically heterogeneous collagenopathy characterized by ophthalmic, auditory, skeletal, and orofacial abnormalities. STL is mainly inherited in an autosomal dominant pattern with mutations in the COL2A1, COL11A1, and COL11A2 genes. Autosomal recessive forms are rare. However, 19 patients have been reported to date, with STL caused by homozygous or compound heterozygous mutations in genes that encode for the three chains of type IX collagen: COL9A1, COL9A2, and COL9A3. Methods Genetic analysis was performed using the next‐generation sequencing of 166 genes associated with skeletal disorders and sequenced on an Ion Torrent S5 system with a minimum coverage of 100X. The two variants in the COL9A3 gene identified in the proband and the parents were confirmed by Sanger sequencing on an ABI3130xl sequencer. Results We describe a novel case of autosomal recessive Stickler syndrome caused by two undescribed mutations in the COL9A3 gene: c.268C>T (p.Arg90Ter) and c.1729C>T (p.Arg577Ter). The clinical features included severe sensorineural hearing loss, high myopia, vitreoretinal degeneration, and early‐onset arthropathy of the lower limbs. Radiography revealed mild spondyloepiphyseal dysplasia. Conclusion This case further expands the mutational and phenotypic spectrum of COL9A‐associated STL with a more severe presentation.

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The amount of human long noncoding RNA (lncRNA) genes is comparable to protein-coding; however, only a small number of lncRNAs are functionally annotated. Previously, it was shown that lncRNAs can participate in many key cellular processes, including regulation of gene expression at transcriptional and post-transcriptional levels. The lncRNA genes can contain small open reading frames (sORFs), and recent studies demonstrated that some of the resulting short proteins could play an important biological role. In the present study, we investigate the widely expressed lncRNA LINC00493. We determine the structure of the LINC00493 transcript, its cell localization and influence on cell physiology. Our data demonstrate that LINC00493 has an influence on cell viability in a cell-type-specific manner. Furthermore, it was recently shown that LINC00493 has a sORF that is translated into small protein SMIM26. The results of our knockdown and overexpression experiments suggest that both LINC00493/SMIM26 transcript and protein affect cell viability, but in the opposite manner.