ZSCAN10 deficiency causes a neurodevelopmental disorder with characteristic oto-facial malformations.

Neurodevelopmental disorders are major indications for genetic referral and have been linked to more than 1,500 loci including genes encoding transcriptional regulators. The dysfunction of transcription factors often results in characteristic syndromic presentations, however, at least half of these patients lack a genetic diagnosis. The implementation of machine learning approaches has the potential to aid in the identification of new disease genes and delineate associated phenotypes. Next generation sequencing was performed in seven affected individuals with neurodevelopmental delay and dysmorphic features. Clinical characterization included reanalysis of available neuroimaging datasets and 2D portrait image analysis with GestaltMatcher. The functional consequences of ZSCAN10 loss were modelled in mouse embryonic stem cells (mESC), including a knock-out and a representative ZSCAN10 protein truncating variant. These models were characterized by gene expression and Western blot analyses, chromatin immunoprecipitation and quantitative PCR (ChIP-qPCR), and immunofluorescence staining. Zscan10 knockout mouse embryos were generated and phenotyped. We prioritized bi-allelic ZSCAN10 loss-of-function variants in seven affected individuals from five unrelated families as the underlying molecular cause. RNA-Seq analyses in Zscan10-/- mESCs indicated dysregulation of genes related to stem cell pluripotency. In addition, we established in mESCs the loss-of-function mechanism for a representative human ZSCAN10 protein truncating variant by showing alteration of its expression levels and subcellular localization, interfering with its binding to DNA enhancer targets. Deep phenotyping revealed global developmental delay, facial asymmetry, and malformations of the outer ear as consistent clinical features. Cerebral MRI showed dysplasia of the semicircular canals as an anatomical correlate of sensorineural hearing loss. Facial asymmetry was confirmed as a clinical feature by GestaltMatcher and was recapitulated in the Zscan10 mouse model along with inner and outer ear malformations. Our findings provide evidence of a novel syndromic neurodevelopmental disorder caused by bi-allelic loss-of-function variants in ZSCAN10.

Variant Classification Discordance: Contributing Factors and Predictive Models.

An ever-growing catalog of human variants is hosted in the ClinVar database. In this database, submissions on a variant are combined into a multisubmitter record; and in the case of discordance in variant classification between submitters, the record is labeled as conflicting. The current study used ClinVar data to identify characteristics that would make variants more likely to be associated with the conflict class of variants. Furthermore, the Extreme Gradient Boosting algorithm was used to train classifier models to provide prediction of classification discordance for single submission variants in ClinVar database. Population allele frequency, the gene harboring the variant, variant type, consequence on protein, variant deleteriousness score, first submitter identity, and submission count were associated with conflict in variant classification. Using such features, the optimized classifier showed accuracy on the test set of 88% with the weighted average of precision, recall, and f1-score of 0.84, 0.88, and 0.85, respectively. There were pronounced associations between variant classification discordance and allele frequency, gene type, and the identity of the first submitter. The study provides the predicted discordance status for single-submitter variants deposited in ClinVar. This approach can be used to assess whether single-submitter variants are likely to be supported, or in conflict with, future entries; this knowledge may help laboratories with clinical variant assessment.

Immunohistochemical Assays for Bladder Cancer Molecular Subtyping: Optimizing Parsimony and Performance of Lund Taxonomy Classifiers.

Transcriptomic and proteomic profiling classify bladder cancers into luminal and basal molecular subtypes, with controversial prognostic and predictive associations. The complexity of published subtyping algorithms is a major impediment to understanding their biology and validating or refuting their clinical use. Here, we optimize and validate compact algorithms based on the Lund taxonomy, which separates luminal subtypes into urothelial-like (Uro) and genomically unstable (GU). We characterized immunohistochemical expression data from two muscle-invasive bladder cancer cohorts (n=193, n=76) and developed efficient decision tree subtyping models using 4-fold cross-validation. We demonstrated that a published algorithm using routine assays (GATA3, KRT5, p16) classified basal/luminal subtypes and basal/Uro/GU subtypes with 86%-95% and 67%-86% accuracies, respectively. KRT14 and RB1 are less frequently used in pathology practice but achieved the simplest, most accurate models for basal/luminal and basal/Uro/GU discrimination, with 93%-96% and 85%-86% accuracies, respectively. More complex models with up to eight antibodies performed no better than simpler two- or three-antibody models. We conclude that simple immunohistochemistry classifiers can accurately identify luminal (Uro, GU) and basal subtypes and are appealing options for clinical implementation.

Association of rs2954029 and rs6982502 Variants with Coronary Artery Disease by HRM Technique: A GWAS Replication Study in an Iranian Population.

Background: Genome-wide association studies (GWAS) have been the primary tool for an unbiased study of the genetic background of coronary artery disease (CAD). They have identified a list of single-nucleotide polymorphisms (SNPs) associated with coronary artery disease (CAD). In this study, we aimed to replicate the association of rs2954029 and rs6982502, a GWAS identified SNP, to CAD in an Iranian population. Methods: A sample of 285 subjects undergoing coronary angiography, including 134 CAD patients and 151 healthy. The genotype determination of rs2954029 and rs6982502 SNPs performed using the high-resolution melting analysis (HRM) technique. Results: Our results revealed that the TT genotype of rs2954029 (p= 0.009) and rs6982502 (p< 0.001) were significantly higher in CAD patients compared with controls. Binary logistic regression showed that rs6982502 and rs2954029 increase the risk of CAD incidence (2.470 times, p= 0.011, 95% CI= [1.219-4.751], and 2.174 times, p= 0.033, 95% CI= [1.066-4.433] respectively). After adjusting for confounders, we found that rs6982502 and rs2954029 are significantly associated with CAD risk. Conclusion: These data showed that the TT genotype of rs2954029 and rs6982502 is associated with the risk of CAD in a hospital-based sample of the Iranian population, which has replicated the result of recent GWAS studies.

Mutually exclusive mutation profiles define functionally related genes in muscle invasive bladder cancer.

Muscle Invasive bladder cancer is known to have an abundance of mutations, particularly in DNA damage response and chromatin modification genes. The role of these mutations in the development and progression of the disease is not well understood. However, a mutually exclusive mutation pattern between gene pairs could suggest gene mutations of significance. For example, a mutually exclusive mutation pattern could suggest an epistatic relationship where the outcome of a mutation in one gene would have the same outcome as a mutation in a different gene. The significance of a mutually exclusive relationship was determined by establishing a normal distribution of the conditional probabilities for having a mutation in one gene and not the other as well as the reverse relationship for each gene pairing. Then these distributions were used to determine the sigma-magnitude of standard deviation by which the observed value differed from the expected, a value that can also be interpreted as the 'p-value'. This approach led to the identification of mutually exclusive mutation patterns in KDM6A and KMT2D as well as KDM6A and RB1 that suggested the observed mutation pattern did not happen by chance. Upon further investigation of these genes and their interactions, a potential similar outcome was identified that supports the concept of epistasis. Knowledge of these mutational interactions provides a better understanding of the mechanisms underlying muscle invasive bladder cancer development, and may direct therapeutic development exploiting genotoxic chemotherapy and synthetic lethality in these pathways.

Variation in the expression level of MALAT1, MIAT and XIST lncRNAs in coronary artery disease patients with and without type 2 diabetes mellitus.

Background: The MALAT1, MIAT, and XIST long noncoding RNAs (lncRNAs) participate in the pathogenesis of complex diseases and also serve as diagnostic markers. The study aimed to assess their expressions in CAD patients with or without T2DM against diabetic and non-diabetic controls.Methods: The expression levels of three lncRNAs in 50 CAD patients (with or without diabetes) and 50 non-CAD subjects (with or without diabetes) were evaluated by using the TaqMan Assay method.Results: MALAT1 and MIAT were upregulated in CAD patients (p Value= .0008 and .0078, respectively). The expression level of XIST was significantly elevated diabetic compared to non-diabetic CAD patients (p Value= .0003). MALAT1 gene had the highest diagnostic power for discrimination of CAD patients from controls (AUC= 0.682, p Value=.001).Conclusions: The current study supports the participation of lncRNAs in the pathogenesis of CAD and T2DM and highlights their potential as diagnostic biomarkers.

Up-regulation of FOXN3-AS1 in invasive ductal carcinoma of breast cancer patients.

Oncogenic and tumor-suppressive roles of long non-coding RNA make them an appropriate target for expression analysis in cancer studies. In this study, we selected two lncRNAs (EMX2OS and FOXN3-AS1) that are resided near the GWAS-identified SNPs for breast cancer (rs2901157 and rs141061110). These transcripts have been identified in different cancer types as either oncogenes or tumor suppressors. In the present investigation, we aimed to quantify the expression level of EMX2OS and FOXN3-AS1 in 44 breast cancer samples and normal adjacent tissues (ANCTs). The FOXN3-AS1 expression level was significantly increased in breast cancer samples compared with ANCTs (P value = 0.02), Also its amounts could distinguish two sets of samples with an accuracy of 70% (P value = 0.009). We have found an association between FOXN3-AS1 expression and tumor size (P value = 0.02). On the other hand, no significant differences were found in the EMX2OS expression level between two sets of samples (P value = 0.44); however, EMX2OS expression level has a significant association with the age of the patients (P value = 0.03). According to our result, FOXN3-AS1 can be demonstrated as a probable diagnostic marker in breast cancer so we suggest further functional studies to find the precise role of these lncRNAs in breast cancer progression.

IFNG-AS1 and MAF4 long non-coding RNAs are upregulated in acute leukemia patients who underwent bone marrow transplantation.

PURPOSE OF THE STUDY: Acute graft versus host disease (aGVHD) is an immune-mediated reaction that results in impaired immune and body function after allogeneic hematopoietic stem cell transplantation (allo-HSCT). lncRNAs have been discovered as particular T cell regulators, and alloreactive T cells have been known as a critical factor in aGVHD. As a result, we investigated the importance of lnc-MAF4 and IFNG-AS1 expression levels in aGVHD patients versus non-aGVHD patients. MATERIAL AND METHODS: This research included 38 patients with hematological disorders who were undergoing primary allo-HSCT. Human identical siblings or unrelated donors were used to collect stem cell. Samples were taken within days 0, 7, 14, 28, and 52±8 after transplantation. The expression of lncRNA levels was measured using the QRT-PCR technique. And the data were analyzed using GraphPad Prism 6 RESULTS: Our data revealed that LncRNA MAF4 and INFG-AS1 expression levels in aGVHD were not significantly different compared to the non-GVHD group immediately after transplantation, nor at day 7 or 14. However, the aGVHD group showed an overt up-regulation of the two lncRNAs on samples taken at day 28 and 52±8 compared to non-GVHD patients. DISCUSSION: Since the intracellular pathway of these lncRNAs shows a direct relationship with the IFNγ cytokine production resulting in differentiation to TH1 cells and inhibition of differentiation to TH2 cells, they can be, therefore, considered as suitable molecular candidates for the prediction of aGVHD in patients receiving HSCT.

Genotype-phenotype associations in hereditary spastic paraplegia: a systematic review and meta-analysis on 13,570 patients.

AIMS: The hereditary spastic paraplegias (HSPs) are a heterogeneous group of inherited neurodegenerative disorders. Although, several genotype-phenotype studies have carried out on HSPs, the association between genotypes and clinical phenotypes remain incomplete since most studies are small in size or restricted to a few genes. Accordingly, this study provides the systematic meta-analysis of genotype-phenotype associations in HSP. METHODS AND RESULTS: We retrieved literature on genotype-phenotype associations in patients with HSP and mutated SPAST, REEP1, ATL1, SPG11, SPG15, SPG7, SPG35, SPG54, SPG5. In total, 147 studies with 13,570 HSP patients were included in our meta-analysis. The frequency of mutations in SPAST (25%) was higher than REEP1 (3%), as well as ATL1 (5%) in AD-HSP patients. As for AR-HSP patients, the rates of mutations in SPG11 (18%), SPG15 (7%) and SPG7 (13%) were higher than SPG5 (5%), as well as SPG35 (8%) and SPG54 (7%). The mean age of AD-HSP onset for ATL1 mutation-positive patients was earlier than patients with SPAST, REEP1 mutations. Also, the tendency toward younger age at AR-HSP onset for SPG35 was higher than other mutated genes. It is noteworthy that the mean age at HSP onset ranged from infancy to adulthood. As for the gender distribution, the male proportion in SPG7-HSP (90%) and REEP1-HSP (78%) was markedly high. The frequency of symptoms was varied among patients with different mutated genes. The rates of LL weakness, superficial sensory abnormalities, neuropathy, and deep sensory impairment were noticeably high in REEP1 mutations carriers. Also, in AR-HSP patients with SPG11 mutations, the presentation of symptoms including pes cavus, Neuropathy, and UL spasticity was higher. CONCLUSION: Our comprehensive genotype-phenotype assessment of available data displays that the mean age at disease onset and particular sub-phenotypes are associated with specific mutated genes which might be beneficial for a diagnostic procedure and differentiation of the specific mutated genes phenotype among diverse forms of HSP.

MicroRNA-copy number variations in coronary artery disease patients with or without type 2 diabetes mellitus.

BACKGROUND: An important cause of Coronary Artery Disease (CAD) is Type 2 Diabetes Mellitus (T2DM). The aim of this study was the evaluation of copy number variations (CNVs) of hsa-miR-93, hsa-miR-122, hsa-miR-192 in CAD patients with or without T2DM. METHODS: CNVs of three micro-RNAs in 50 CAD patients and 50 non-CAD subjects both with and without diabetes were evaluated by real-time PCR and compared in three comparison groups namely 1, 2 and 3 (including comparison between CAD and non-CAD, diabetic CAD and non-diabetic CAD and between diabetic CAD and diabetic non-CAD subjects, respectively). RESULTS: There were significant differences in CNVs of hsa-miR-93 between cases and controls in comparison groups 1 and 3 (p = .0310 and .0232, respectively), for hsa-miR-122 in all comparison groups, and for hsa-miR-192 in comparison group 3 (p = .0181). CONCLUSION: We showed the association of these microRNA-CNVs with CAD, T2DM or both simultaneously.

Hsa-miR-27a-3p and epidermal growth factor receptor expression analysis in glioblastoma FFPE samples.

AIM: Glioblastoma multiforme (GBM) is the most invasive type of glial tumors. MicroRNAs as the small, noncoding RNAs have been revealed that play an important role in tumorigenic processes. So, they may be used as potential biomarkers for detection and prognosis of cancers at the early stages. In addition, they can be applied as therapeutic targets. In the present study, the expression levels of hsa-miR-27a-3p and EGFR were investigated in GBM. METHODS: Real-time RT-PCR was applied to evaluate hsa-miR-27a-3p and EGFR expressions in the formalin-fixed paraffin-embedded (FFPE) tissue samples obtained from 50 GBM and 50 normal people. RESULTS: The expression level of hsa-miR-27a-3p and EGFR was significantly different between cases and controls. Positive association was found between gene expressions and immunohistochemistry markers, such as Ki67 and glial fibrillary acidic protein, except for IDH1 status. CONCLUSION: We showed the association of hsa-miR-27a-3p and EGFR with GBM and it can be concluded that they have a promising potential to use as primary cancer biomarkers.

Whole-exome sequencing identified a novel mutation of MLH1 in an extended family with lynch syndrome.

Hereditary nonpolyposis colorectal cancer or Lynch syndrome is autosomal dominant cancer predisposition syndrome characterized by early onset of colorectal cancer and neoplasia in other organs. This condition typically caused by germline mutations in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2. To date, a considerable number of MLH1 gene mutations have been found to be associated with Lynch syndrome. We were aimed at identifying a genetic mutation in an extended Iranian family affected by Lynch syndrome-related cancers. Here, we applied whole-exome sequencing to identifying mutation in the proband. Furthermore, we applied Sanger sequencing to validate the candidate variant. We found a heterozygous novel single nucleotide deletion (c.206delG) in the exon two of the MLH1 gene in the proband. Also, Sanger sequencing analysis showed that this mutation has segregated in all affected family members. The mutation (c.206delG:p.R69fs) may create a premature stop codon followed by the formation of a truncated (p.R69fs) Mlh1 protein. Our findings expand the mutational spectra of MLH1 gene related Lynch syndrome which is vital for screening and genetic diagnosis of the disease.

SUCLG1 mutations and mitochondrial encephalomyopathy: a case study and review of the literature.

The mitochondrial encephalomyopathies represent a clinically heterogeneous group of neurodegenerative disorders. The clinical phenotype of patients could be explained by mutations of mitochondria-related genes, notably SUCLG1 and SUCLA2. Here, we presented a 5-year-old boy with clinical features of mitochondrial encephalomyopathy from Iran. Also, a systematic review was performed to explore the involvement of SUCLG1 mutations in published mitochondrial encephalomyopathies cases. Genotyping was performed by implementing whole-exome sequencing. Moreover, quantification of the mtDNA content was performed by real-time qPCR. We identified a novel, homozygote missense variant chr2: 84676796 A > T (hg19) in the SUCLG1 gene. This mutation substitutes Cys with Ser at the 60-position of the SUCLG1 protein. Furthermore, the in-silico analysis revealed that the mutated position in the genome is well conserved in mammalians, that implies mutation in this residue would possibly result in phenotypic consequences. Here, we identified a novel, homozygote missense variant chr2: 84676796 A > T in the SUCLG1 gene. Using a range of experimental and in silico analysis, we found that the mutation might explain the observed phenotype in the family.

The genetic basis for the inverse relationship between rheumatoid arthritis and schizophrenia.

INTRODUCTION: Rheumatoid arthritis is a common autoimmune disease and schizophrenia is a relatively common and debilitating neurological disorder. There are several common features between rheumatoid arthritis and schizophrenia. The inverse relationship between rheumatoid arthritis and schizophrenia has been replicated in several studies. Despite evidence for an inverse epidemiological relationship and negative correlations for risk between rheumatoid arthritis and schizophrenia, there are no biological data that directly support this inverse relationship. MATERIALS AND METHODS': We meta-analyzed the genome-wide association studies to investigate the shared association loci between rheumatoid arthritis and schizophrenia at the genome-wide scale. Rheumatoid arthritis- and schizophrenia-associated loci in most recent genome-wide association studies of rheumatoid arthritis and schizophrenia were tested. Genetic risk score analysis was also conducted to investigate the collective contribution of schizophrenia risk loci to rheumatoid arthritis risk. RESULTS: Rheumatoid arthritis and schizophrenia meta-genome-wide association study showed a significant peak at the major histocompatibility complex locus on chromosome 6 in both rheumatoid arthritis-schizophrenia meta-genome-wide association study and inverted meta-genome-wide association study datasets. Testing rheumatoid arthritis- and schizophrenia-associated loci outside the human leukocyte antigen region showed no association with both rheumatoid arthritis and schizophrenia at a genome-wide level of significance. Weighted genetic risk scores showed no evidence for a statistically significant association between rheumatoid arthritis and schizophrenia. CONCLUSION: The finding of our study is consistent with the role of the major histocompatibility complex locus in the genetic correlation between rheumatoid arthritis and schizophrenia, and suggests that either schizophrenia has an autoimmune basis and/or rheumatoid arthritis has an active neurological component.

An updated review of the H19 lncRNA in human cancer: molecular mechanism and diagnostic and therapeutic importance.

Accumulating evidence has reported that H19 long non-coding RNA (lncRNA) expression level is deregulated in human cancer. It has been also demonstrated that de-regulated levels of H19 could affect cancer biology by various mechanisms including microRNA (miRNA) production (like miR-675), miRNA sponging and epigenetic modifications. Furthermore, lncRNA could act as a potential diagnosis and prognosis biomarkers and also a candidate therapeutic approach for different human cancers. In this narrative review, we shed light on the molecular mechanism of H19 in cancer development and pathogenesis. Moreover, we discussed the expression pattern and diagnostic and therapeutic importance of H19 as a potential biomarker in a range of human malignancies from breast to osteosarcoma cancer.

High-intensity interval training (HIIT) effectively enhances heart function via miR-195 dependent cardiomyopathy reduction in high-fat high-fructose diet-induced diabetic rats.

Aims: Regarding the fact that up-regulation of miR-195 in diabetic hearts has a potential role in diabetic cardiomyopathy, the present study investigated whether continuous endurance training (CET) and high-intensity interval training (HIIT) reduces miR-195 expression and which exercise is effective in this regard.Methods: Diabetes was induced by high-fat high-fructose diet (HFHFD). Then, the rats were sub-divided into three categories; sedentary (HFHFD + SED), continuous endurance training (HFHFD + CET), and high-intensity interval training group (HFHFD + HIIT). After eight weeks of running, expression of miR-195 and myocardial function were evaluated.Results: HIIT effectively decreases the expression of miR-195 and increases the expression of Sirt1 and BCL-2 in diabetic rats compared with CET. Our results showed that HIIT compared with CET increases left ventricular ejection fraction (LVEF%) and fractional shortening (FS%).Conclusions: Our results indicated that exercise, especially HIIT is an appropriate strategy for reducing miR-195 and improving myocardial function in diabetic rats compared with CET.

Potential Prognostic Role for SPOP, DAXX, RARRES1, and LAMP2 as an Autophagy Related Genes in Prostate Cancer.

PURPOSE: Autophagy plays a critical role in PCa development. DAXX has a potent pro-survival effect by enhancing cell growth in PCa via suppression of autophagy. Here, we depicted a network governed by DAXX and SPOP by which the autophagy pathway is suppressed through the ubiquitination and modulation of key cellular signaling pathways mediators including LAMP2 and RARRES1. MATERIALS AND METHODS: Through network-based bioinformatics approaches, the expression levels of DAXX, RARRES1, LAMP2, and SPOP genes was assessed in 50 PCa tissues and 50 normal adjacent from the same sample as well as 50 benign prostatic hyperplasia (BPH) tissues by quantitative RT-PCR. The normal adjacent tissues were taken from regions more than 5mm away from the bulk of those tumor tissues with clearly distinct margins. RNA extraction, cDNA synthesis and Real-time Quantitative RT-PCR were done for assessment of gene expression. To evaluate the primary gene network centered on autophagy pathway, according to the Query-dependent weighting algorithm, these two networks were integrated with Cytoscape 3.4 software. RESULTS: We found that in PCa tissues the DAXX expression level was significantly increased (P < 0.001) and the expressions of SPOP, RARRES1, and LAMP2 were significantly down-regulated, when compared to both control groups including normal adjacent and BPH tissues. Moreover, significant correlations were observed between expression levels of all four genes. Additionally, ROC curve analysis revealed that LAMP2 had the most sensitivity and specificity. CONCLUSION: These findings suggest that the contribution of SPOP, DAXX, RARRES1, and LAMP2 together could be a putative regulatory element acting as a prognostic signature and therapeutic target in PCa.

The effects of somatic mutations on EGFR interaction with anti-EGFR monoclonal antibodies: Implication for acquired resistance.

A number of mutations in the epidermal growth factor receptor (EGFR) have been identified that imparts resistance to anti-EGFR monoclonal antibodies (mAbs) in clinical and preclinical samples. Primary or acquired resistance to targeted therapy will eventually limit the clinical benefit of anticancer mAbs. The aim of the current study was to perform computational analysis to investigate the structural implications of the EGFR somatic mutations on its complexes with the four anti-EGFR mAbs (Cetuximab, Panitumumab, Necitumumab, and Matuzumab). Docking analysis and molecular dynamics (MD) simulations were performed to understand the plausible structural and dynamical implications caused by somatic mutations available in the Catalogue of Somatic Mutations in Cancer database on the EGFR and anti-EGFR mAbs. We found that EGFRS492R and EGFRV441I in complex with Cetuximab, EGFRR377S and EGFRS447Y in complex with Panitumumab, and EGFRV441I in complex with Necitumumab have a weakest binding affinity in comparison to EGFRWT in complex with the relevant mAb. Taken together with the results obtained from docking analysis and MD simulations, the present findings may suggest that, the S492R and V441I mutations confer resistance to Cetuximab, R377S and S447Y mutations mediate resistance to Panitumumab and finally, V441I mutation also confers resistance to Necitumumab.

Homozygous Mutation in TWNK Cases Ataxia, Sensorineural Hearing Loss and Optic Nerve Atrophy.

The TWNK (C10orf2) gene encodes Twinkle, an essential helicase for mtDNA replication. Homozygous mutations in TWNK can lead to mitochondrial DNA depletion syndrome 7 (MTDPS7) that usually manifests as Infantile onset spinocerebellar ataxia (IOSCA). Here, we report a 15-year-old Iranian boy with three main symptoms; ataxia, sensorineural hearing loss and optic nerves atrophy which were accompanied by other symptoms including flexion contracture, dysarthric speech, nystagmus, dystonia and borderline intellectual disability. Whole exome sequencing (WES) revealed a homozygous mutation in his TWNK gene. The mutation was a transversion which replaced a C with A (NM_021830.4 (TWNK):c.874C>A). This nucleotide substitution results in replacing a Threonine with Proline in codon 292 of Twinkle protein (p.Pro292Thr). In silico analyses showed that this amino acid change in Twinkle could be deleterious and disease-causing; therefore, we attribute the symptoms of our patient to this mutation. Our study extended the homozygous mutation spectrum of the TWNK gene that leads to IOSCA.

Deregulation of long noncoding RNA SNHG17 and TTC28-AS1 is associated with type 2 diabetes mellitus.

Long noncoding RNAs (lncRNAs) have emerged as key players in several biological processes and complex diseases including type 2 diabetes mellitus (T2DM). The purpose of this study was to investigate the expression levels of SNHG17 and TTC28-AS1 in T2DM patients. Quantitative real-time RT-PCR analysis was performed using peripheral blood mononuclear cells (PBMCs) samples from patients diagnosed with T2DM and healthy controls. Binary logistic regression analysis was carried out to determine the odds of development of T2DM based on expression levels of lncRNAs and clinical characteristic of the subjects. Spearman's correlation analysis was used to clarify the correlation between SNHG17 and TTC28-AS1 expressions to metabolic features. We found that SNHG17 and TTC28-AS1were down-regulated in the T2DM group compared to the healthy control group. The logistic regression revealed that body mass index (BMI), systolic blood pressure (SBP), fasting blood glucose (FBG) and TTC28-AS1 expression substantially affect T2DM susceptibility. Furthermore, expression of SNHG17 was negatively correlated with high-density lipoprotein cholesterol (HDL-C) and expression of TTC28-AS1 was positively correlated with low-density lipoprotein cholesterol (LDL-C). Decreased expressions of lncRNAs TTC28-AS1 and SNHG17 in T2DM are possibly associated with the development of T2DM.