分子遺伝医学

Mutations in the MTM1 gene, encoding the phosphoinositide phosphatase myotubularin, are responsible for the X-linked centronuclear myopathy (XLCNM) or X-linked myotubular myopathy (XLMTM). The MTM1 gene was first identified in 1996 and its function as a PtdIns3P and PtdIns(,5)P2 phosphatase was discovered in 2000. In recent years, very important progress has been made to set up good models to study MTM1 and the XLCNM disease such as knockout or knockin mice, the Labrador Retriever dog, the zebrafish and the yeast Saccharomyces cerevisiae. These helped to better understand the cellular function of MTM1 and of its four conserved domains: PH-GRAM (Pleckstrin Homology-Glucosyltransferase, Rab-like GTPase Activator and Myotubularin), RID (Rac1-Induced recruitment Domain), PTP/DSP (Protein Tyrosine Phosphatase/Dual-Specificity Phosphatase) and SID (SET-protein Interaction Domain). This review presents the cellular function of human myotubularin MTM1 and its yeast homolog yeast protein Ymr1, and the role of MTM1 in the centronuclear myopathy (CNM) disease.

Despite the high efficiency of tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia, 20-25% of patients develop drug resistance resulting in therapy failure. Besides mutations of the BCR-ABL1 kinase domain, the abnormal epigenetic regulation of the expression of critical genes for cell proliferation and survival has a central role in the disease pathogenesis and progression towards the drug resistant phenotype. Such epigenetic changes have the potential to be modulated by specific drugs including demethylating agents and histone deacetylase inhibitors. Here the current knowledge on the BCR-ABL1-associated methylation status is reviewed.

Renal Cell Carcinoma (RCC) represents a significant cause of cancer related deaths in the United States and worldwide. Current conventional imaging modalities including Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) reveal high resolution images of structural abnormalities; but these same modalities often fail to provide the adequate accuracy, specificity and sensitivity for diagnosing RCC from benign lesions. This has prompted ongoing investigation of molecular imaging modalities as a non-invasive alternative to biopsy. Initial use of glucose-based imaging agents has proven insufficient for common RCC histologies which have led to the development of targeted radiotracers to improve sensitivity of these scans. Current trials are ongoing to characterize the best use of these new targeted agents. In addition, novel radiotracer agents to evaluate renal perfusion, renal tubular function are being created and investigated.

We describe two cases where clinical diagnoses were carried out (Rett syndrome-like and Nicolaides-Baraitser syndrome) with no identified mutation respectively in the CDKL5 and the SMARCA2 genes. Conversely a chromosomal microdeletion with contiguous deletion of a part of these two genes was found by arrayCGH in each corresponding case. The aim of this report is then to highlight the possible implication of chromosomal microdeletions with contiguous gene deletions in dominant pathologies where no mutation is found in the causative gene.

Genomics in Atrial Fibrillation Atrial fibrillation (AF) carries a significant burden in the form of morbidity, mortality, and cost to the healthcare system. According to the Center for Disease Control, AF is the most common cardiac arrhythmia in the United States with an incidence of 2.26 million people in 2010 that is expected to increase to 12 million people by 2050 [1]. The mortality rate from AF as a primary or secondary cause of death is increasing, as is the cost burden to the healthcare system [1]. It is estimated that in the year 2005, the cost to the U.S. healthcare system for treating AF was $6.65 billion

DNA (cytosine 5-) MethylTransferase 1 (DNMT1) maintains the pre-existing methyl marks onto daughter strands by faithfully copying the methylation pattern from hemimethylated DNA during replication phase. The fundamental role of DNA methylation in cell physiology makes a controlled regulation of DNMT1 necessary. DNMT1 loss and global DNA hypomethylation are correlated with genomic instability in cancer. This mini review aims to provide a scenario of the mechanisms whereby DNMT1 dysfunction could induce https://www.omicsonline.org/open-access/genomics-of-colorectal-cancer-in-african-americans-2469-9853-1000133.php?aid=80577 instability so as to clarify its functions and understand the dynamics of DNA methylation at cellular level with a focus on cancer.

Introduction and Objectives: Hypertrophic cardiomyopathy is the most common genetic cardiovascular disease. Mutations have been described in at least 27 genes that can encode sarcomere proteins, mitochondrial proteins and proteins that control calcium handling. This report shows a family with Hypertrophic cardiomyopathy in the presence of sudden death. Methods: We performed a clinical, genetic and molecular biology to establish the phenotypic and genotypic commitment of this disease. We analyzed a total of 592 mutations in 16 genes spread ACTC, GLA, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYLK2, MYO6, PRKAG2, TCAP, TNN1, TNNI3, TNN2, TPM1 and TTN. Results: We determined phenotypic and genotypic characteristics of 37 members belonging to one family in five generations. Lys247Arg (K247R) mutation was found in 13 family members (38.23%) of which 3 had hypertrophy on echocardiography, but two patients had hypertrophy and they did not have the mutation. Moreover, a patient carries the mutation but the mother does not. The father (not related to the family) carries this mutation. Conclusions: We present a Colombian family with hypertrophic cardiomyopathy and sudden death where described causal mutations in the sarcomeric genes were evaluated. K247R genetic variant in the Troponin T type 2 gene was found with no correspondence to the phenotypic expresion of the disease in the family.

Stem cells have been proposed as a promising source for cell therapy. Understanding the biological processes that commit stem cells to differentiate into a particular cell type is essential for the successful repair of injured tissue, and even for whole organogenesis. Cellular differentiation can be modeled as a network of regulatory circuits that direct various steps of gene expression and mediate the spatiotemporal control of a cell’s proteome. In this minireview, we discuss the current aspects of posttranscriptional regulation of gene expression in stem cells, with an emphasis on translational regulation. Several data supports the idea that a significant percentage of genes have their expression controlled at the translational level during stem cell commitment and differentiation. We focus on strategies using polysome and ribosome profiling to measure translational rates and to unravel the dynamics of this process.

The growth hormone secretagogue receptor 1a (GHSR1a) is involved in many important functions including growth hormone (GH) secretion and appetite regulation and other important functions. We reveal herein, the unravelling of bovine-specific 5’untranslated region (5’UTR) microsatellite polymorphisms, a 3bp-indel in exon 1 (DelR242) and two different kinds of transcripts of the GHSR1a gene (spliced, without a microsatellite with in the 5’UTR (GHSR1a); and non-spliced, with the microsatellite (GHSR1b)). A number of 17 alleles ((TG)10~33 ) in the 5’UTR microsatellite was found in 11 cattle breeds. Furthermore, we found the DelR242 (3R) allele, a truncated 3- arginine residue (3R) (major type: 4 arginine residues (4R)) within the intracellular loop 3 of GHSR1a protein in Japanese Shorthorn with a high frequency of 0.43 compared to the low frequency of 0.00~0.09 in other cattle breeds. We carried out a genetic association study between the 5’UTR microsatellite and growth and carcass traits in 1,285 steers. Statistical analysis revealed that the 5’UTR microsatellite locus had a significant additive effect on carcass weight (CW) and average daily gain (ADG). The 19-TG allele had a significantly desirable effect on these traits. We proposed a translational hypothesis that the association is due to differences in the secondary structure of GHSR1b mRNA among the GHSR1a gene haplotypes. We also examined age-related changes in the expressions of GHSR1a and GHSR1b in many cattle tissues. The GHSR1a mRNA expression in the arcuate nucleus of postweaning calves was more than 10-fold higher than those of pre-weaning calves and cows. In peripheral tissues, there were 3 marked differences in mRNA expression between cattle, humans and mice, as follows: (1) the GHSR1a mRNA expression in the liver is high in cattle and very low in humans and mice; (2) the GHSR1b mRNA expression in the liver is low in cattle and high in humans; (3) the GHSR1b mRNA expression in the pancreas is very high in cattle.

Development of New Animal Models of Atherosclerosis Atherosclerosis and complications associated with this pathology, such as coronary artery disease, remains a leading cause of morbidity and mortality in the world [1]. Dyslipidemia is one of the main risk factors leading to development of the atherosclerosis [2,3]. Peripheral (non-hepatic) cells, including arterial and aortic cells, obtain cholesterol from either de novo synthesis or from uptake of plasma lipoproteins. To prevent atherosclerosis, excess cholesterol must be removed from cells. This process takes place through the reverse cholesterol transport pathway [4,5], a process whereby cells efflux excess cholesterol to HDL, which subsequently delivers cholesterol to the liver for excretion into the bile.

Unacylated Ghrelin (UnAG) Peripheral arterial disease (PAD) is a major clinical problem and a significant health care cost worldwide [1]. PAD is the result of a progressive occlusion of the peripheral arteries driven by atherosclerosis [2]. This, in turn, leads to a gradual reduction of blood supply to the limb and the occurrence of symptoms ranging from intermittent claudication to critical limb ischemia [3]. Moreover, as PAD remains under-diagnosed for many years, muscle damage and ulceration are commonly found. PAD is a common vascular complication in diabetic individuals [4] and its incidence and prevalence are expected to increase due to the spread of diabetes and an aging population [5]. In particular, diabetic patients have a high risk of developing PAD which is more severe and diffuse than in nondiabetic patients [4]. Moreover, the presence of PAD in these patients is associated with an increased morbidity and mortality for cardiovascular diseases [1,4].

Polycystic ovary syndrome is the most common endocrinal disorder and is associated with infertility. Insulin resistance is a key component in the pathogenesis of PCOS and the predisposition to Type 2 diabetes mellitus. The existing literature supports a strong basis of PCOS clusters in families. However, due to the genetic and phenotypic heterogeneity of PCOS and the lack of large cohort studies and identification of specific contributing genes to date have yielded only few conclusive results. Although several loci have been proposed as PCOS genes including CYP11A, the insulin gene, and a region near the insulin receptor, the strongest case can be made for the region near the insulin receptor gene. Insulin receptor substrates proteins (IRS) are critical for insulin mediated signal transduction in insulin target tissues. Several studies have shown that IRS-1 Gly972Arg polymorphism might be the factor causing susceptibility to Type 2 diabetes mellitus (T2DM) and are associated with phenotypic features of
PCOS. In this article we reviewed the current status of the genetic analysis of insulin (INS), insulin  receptor (INSR), insulin receptor substrate (IRS) in relation to polycystic ovary syndrome, an infertility disorder in females.

Administration of live Brucella vaccine is required to prevent the spreadof ruminant brucellosisin affected livestock herds. This study optimized the mouse model to test the protective efficacy of live Brucella vaccine. To optimize the protective efficacy test procedure, the absolute infective doses were determined in mice as 10 Colony Forming Units (CFU)/mouse for B. melitensis 16M and 50 CFU/mouse for B. abortus 2308, which were then used as the challenge doses for the respective strains. The optimal vaccination doses of vaccine Brucellasuis S2 in mice were 102.25 CFU and 103.5 CFU/mouse, which could confer ≥ 80% protection in mice against challenge by B. melitensis 16M or B. abortus 2308, respectively. In addition, challenge with B. melitensis 16M or B. abortus 2308 should occur just at 3.63 weeks and 4.75 weeks post-inoculation, respectively. The protective efficacy test not only was more accurate and took less time but also was consistent with the evaluation index in host animals. Our study indicated that the mouse model could be used to test the protective efficacy of live Brucella vaccines during their production and development.

Background: Etiology of age-related macular degeneration (AMD) is poorly understood, although oxidative stress and environmental risk factors have been implicated. Recently, AhR (arylhydrocarbon receptor) and Nrf2 (nuclear factor erythroid 2-related factor 2) were considered as AMD candidate genes. Transcription products of the AhR-Nrf2 “gene battery” are important in mediating cellular response to oxidative stress. The animal model for AMD (senescence accelerated OXYS rats) was used. Ophthalmoscopy revealed no pathologic changes in OXYS rats’ retinas at the age of 1 month; however, at the age of 3 months, the first signs of retinopathy were recorded in the eyes of all animals tested. The aim of the present study was to determine whether the balance between prooxidizing (AhR-dependent) and antioxidant (Nrf2-dependent) systems plays a crucial role in the onset and/or progression of age-related retinopathy. Methods: In the retina of 1-, 3- and 12- month-old OXYS and Wistar rats mRNA levels of CYP1A1, CYP1A2, CYP1B1, GSTA1, NQO1, ALDH3A1, UGT1A6, UGT1A9, AhR and Nrf2 genes were measured by qRT-PCR. Results: In the retinas of 1-month OXYS rats, the mRNA level of only AhR was reduced when compared with Wistar rats. At the age of 3 months, a decline in the mRNA levels was detected for CYP1A and CYP1A2, but not for CYP1B1 in OXYS rats. mRNA levels of Nrf2, were higher in OXYS rats when compared with Wistar rats. Levels of the genes that are regulated by AhR and Nrf2 (NQO1 and UGT1A6), were reduced when compared with Wistar rats, and GSTA1: mRNA level was increased. Conclusions: The data obtained allow us to conclude that the AhR-Nrf2 “gene battery” may be involved in the pathogenesis of retinopathy in the OXYS rats. One of the triggers for the starting of oxidative stress during the progression of retinopathy may be the inborn reduced level of AhR expression.

Cystatins are the thiol proteinases inhibitors of prime physiologic importance. They are ubiquitously present in mammalian body. They prevent unwanted proteolysis and play important role in several diseases. Regulation of cysteine proteinases and their inhibitors are of utmost importance in diseases like Alzheimer, amlyoid angiopathy and other neurodegenerative disease. Proteinase anti-proteinase imbalance accelerates disease progression. Amitriptylin an antidepressant helps to relieve depression and pain. It is often used to manage nerve pain resulting from cancer treatment. Such injury to nerves causes a burning, tingling sensation. This medication, usually given at bedtime, helps patients to sleep better

In this paper interaction of brain cystatin (BC) with Amytriptyline (AMY) has been studied by UV absorption and fluorescence spectroscopy. In the present study, the effect of drug has been studied to explore AMY induced changes in functional and structural integrity of the cystatin. The fluorescence quenching data is indicative of complex formation between the protein and drug which confirmed the binding of Amytriptyline with brain cystatin. Stern-Volmer analysis of Amytriptyline binding with brain cystatin indicates the presence of static component in the quenching mechanism. The thermodynamic parameters ΔG° (Free energy change) -36.966 KJ/mol indicated that both hydrogen bonds and hydrophobic interactions played a major role in the binding of AMY with BC. Binding investigations give in this work, gives significant information about the conformational changes in cystatin due interaction with the drug.