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Mutational Landscape of Spontaneous Base Substitutions and Small Indels in Experimental Caenorhabditis elegans Populations of Differing Size.

Genetics 2019 Jul;212(3):837-854

Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas 77845.

Experimental investigations into the rates and fitness effects of spontaneous mutations are fundamental to our understanding of the evolutionary process. To gain insights into the molecular and fitness consequences of spontaneous mutations, we conducted a mutation accumulation (MA) experiment at varying population sizes in the nematode Caenorhabditis elegans, evolving 35 lines in parallel for 409 generations at three population sizes (N = 1, 10, and 100 individuals). Here, we focus on nuclear SNPs and small insertion/deletions (indels) under minimal influence of selection, as well as their accrual rates in larger populations under greater selection efficacy. Read More

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Mutational Landscape of Spontaneous Base Substitutions and Small Indels in Experimental Caenorhabditis elegans Populations of Differing Size.

Genetics 2019 Jul;212(3):837-854

Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas 77845.

Experimental investigations into the rates and fitness effects of spontaneous mutations are fundamental to our understanding of the evolutionary process. To gain insights into the molecular and fitness consequences of spontaneous mutations, we conducted a mutation accumulation (MA) experiment at varying population sizes in the nematode Caenorhabditis elegans, evolving 35 lines in parallel for 409 generations at three population sizes (N = 1, 10, and 100 individuals). Here, we focus on nuclear SNPs and small insertion/deletions (indels) under minimal influence of selection, as well as their accrual rates in larger populations under greater selection efficacy. Read More

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Search for Genetic Predictors of Adult Autoimmune Polyendocrine Syndrome in Monozygotic Twins.

Clin Med Insights Endocrinol Diabetes 2021 19;14:11795514211009796. Epub 2021 Apr 19.

Department of Neuroendocrinology and Osteopathies, Endocrinology Research Centre, Moscow, Russia.

Autoimmune polyendocrine syndromes (APS) are a heterogeneous group of diseases characterized by the presence of autoimmune dysfunction of 2 or more endocrine glands and other non-endocrine organs. The components of the syndrome can manifest throughout life: in childhood-APS type 1 (the juvenile type) and in adulthood-APS type 2, 3, and 4 (the adult types). Adult types of APS are more common in clinical practice. Read More

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Second-generation live-attenuated Candid#1 vaccine virus resists reversion and protects against lethal Junín virus infection in guinea pigs.

J Virol 2021 May 5. Epub 2021 May 5.

Montana Biotechnology Center, University of Montana, Missoula, MT, United States

Live-attenuated virus vaccines are highly effective in preventing viral disease but carry intrinsic risks of residual virulence and reversion to pathogenicity. The classically derived Candid#1 virus protects seasonal field workers in Argentina against zoonotic infection by Junín virus (JUNV), but is not approved in the U.S. Read More

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When a maternal heterozygous mutation of the CYP24A1 gene leads to infantile hypercalcemia through a maternal uniparental disomy of chromosome 20.

Mol Cytogenet 2021 May 5;14(1):23. Epub 2021 May 5.

Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics and Reference Center for Developmental Disorders, Normandy Center for Genomic and Personalized Medicine, 76000, Rouen, France.

Background: Infantile hypercalcemia is an autosomal recessive disorder caused either by mutations in the CYP24A1 gene (20q13.2) or in the SLC34A1 gene (5q35.3). Read More

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Oxytocin ameliorates impaired social behavior in a Chd8 haploinsufficiency mouse model of autism.

BMC Neurosci 2021 May 1;22(1):32. Epub 2021 May 1.

Department of Basic Research on Social Recognition and Memory, Research Center for Child Mental Development, Kanazawa University, Kanazawa, 920-8640, Japan.

Background: Autism spectrum disorder (ASD) is characterized by the core symptoms of impaired social interactions. Increasing evidence suggests that ASD has a strong genetic link with mutations in chromodomain helicase DNA binding protein 8 (CHD8), a gene encoding a chromatin remodeler. It has previously been shown that Chd8 haplodeficient male mice manifest ASD-like behavioral characteristics such as anxiety and altered social behavior. Read More

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Bruton's tyrosine kinase regulates gut immune homeostasis through attenuating Th1 response.

Cell Death Dis 2021 Apr 30;12(5):431. Epub 2021 Apr 30.

NUS Graduate School for Integrative Sciences & Engineering (NGS), National University of Singapore, Singapore, Singapore.

Inflammatory bowel disease (IBD) is driven by multiple genetic and environmental risk factors. Patients with mutations in Bruton's tyrosine kinase (BTK) is known to manifest high prevalence of intestinal disorders including IBD. Although BTK mediates the signaling of various immune receptors, little is known how BTK maintains the homeostasis of the gut immune system. Read More

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The Spectrum of Maculopathy in Mitochondrial DNA A3243G Mutation: A Case Series of Six Patients.

Klin Monbl Augenheilkd 2021 Apr 30;238(4):414-417. Epub 2021 Apr 30.

Ophthalmology, Jules Gonin Eye Hospital, Lausanne, Switzerland.

Background: The mitochondrial DNA (mtDNA) A3243G point mutation encompasses a heterogenous group of disorders including mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), maternally inherited diabetes and deafness (MIDD), and, rarely, chronic progressive external ophthalmoplegia (CPEO). Regardless of the clinical phenotype, a specific retinopathy has been associated with the presence of this mitochondrial DNA mutation. We present six female patients exhibiting retinopathy of the A3243G point mutation at various stages. Read More

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A Perspective on Accelerated Aging Caused by the Genetic Deficiency of the Metabolic Protein, OPA1.

Front Neurol 2021 13;12:641259. Epub 2021 Apr 13.

Mitochondria and Vision Lab, School of Optometry and Vision Sciences, Cardiff University, Cardiff, United Kingdom.

Autosomal Dominant Optic Atrophy (ADOA) is an ophthalmological condition associated primarily with mutations in the gene. It has variable onset, sometimes juvenile, but in other patients, the disease does not manifest until adult middle age despite the presence of a pathological mutation. Thus, individuals carrying mutations are considered healthy before the onset of clinical symptoms. Read More

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The role of calcium-sensing receptor signaling in regulating transepithelial calcium transport.

Exp Biol Med (Maywood) 2021 Apr 29:15353702211010415. Epub 2021 Apr 29.

Department of Physiology, University of Alberta, Edmonton T6G 1C9, Canada.

The calcium-sensing receptor (CaSR) plays a critical role in sensing extracellular calcium (Ca) and signaling to maintain Ca homeostasis. In the parathyroid, the CaSR regulates secretion of parathyroid hormone, which functions to increase extracellular Ca levels. The CaSR is also located in other organs imperative to Ca homeostasis including the kidney and intestine, where it modulates Ca reabsorption and absorption, respectively. Read More

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Towards Mutation-Specific Precision Medicine in Atypical Clinical Phenotypes of Inherited Arrhythmia Syndromes.

Int J Mol Sci 2021 Apr 10;22(8). Epub 2021 Apr 10.

Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, Maebashi 371-8511, Gunma, Japan.

Most causal genes for inherited arrhythmia syndromes (IASs) encode cardiac ion channel-related proteins. Genotype-phenotype studies and functional analyses of mutant genes, using heterologous expression systems and animal models, have revealed the pathophysiology of IASs and enabled, in part, the establishment of causal gene-specific precision medicine. Additionally, the utilization of induced pluripotent stem cell (iPSC) technology have provided further insights into the pathophysiology of IASs and novel promising therapeutic strategies, especially in long QT syndrome. Read More

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Clinicopathological features of 70 desmoid-type fibromatoses confirmed by β-catenin immunohistochemical staining and CTNNB1 mutation analysis.

PLoS One 2021 29;16(4):e0250619. Epub 2021 Apr 29.

Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.

Desmoid-type fibromatosis (DF) is a locally aggressive neoplasm characterized by mutations in the CTNNB1 gene, which encodes the β-catenin protein. We reviewed 85 cases of DF and performed Sanger sequencing for detecting mutations in CTNNB1 and immunostaining for detecting β-catenin localization. We included 70 DF samples, of which 56 cases demonstrated nuclear β-catenin localization and 43 cases harboured CTNNB1 mutations. Read More

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A GDF5 frameshift mutation segregating with Grebe type chondrodysplasia and Brachydactyly Type C+ in a 6 generations family: Clinical report and mini review.

Eur J Med Genet 2021 Apr 16:104226. Epub 2021 Apr 16.

Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE) College, PIEAS, Faisalabad, Pakistan. Electronic address:

Different mutations in the Growth/Differentiation Factor 5 gene (GDF5) have been associated with varying types of skeletal dysplasia, including Grebe type chondrodysplasia (GTC), Hunter-Thompson syndrome, Du Pan Syndrome and Brachydactyly type C (BDC). Heterozygous pathogenic mutations exert milder effects, whereas homozygous mutations are known to manifest more severe phenotypes. In this study, we report a GDF5 frameshift mutation (c. Read More

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[CME Laboratory 63/Answers: Diagnostics of Iron Metabolism].

Praxis (Bern 1994) 2021 Apr;110(5):249-250

Institut für Klinische Chemie, Universitätsspital Zürich.

CME Laboratory 63/Answers: Diagnostics of Iron Metabolism Abstract: Iron deficiency is common and affects the course of many chronic diseases. The diagnosis of absolute and manifest iron deficiency anemia can be easily made by measuring hemoglobin and serum ferritin levels. In inflammatory diseases, the diagnosis can be facilitated by additional laboratory parameters such as soluble transferrin receptor. Read More

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Computational Saturation Screen Reveals the Landscape of Mutations in Human Fumarate Hydratase.

J Chem Inf Model 2021 Apr 13;61(4):1970-1980. Epub 2021 Apr 13.

Department of Medical Physics and Biomedical Engineering, UCL, London WC1E 6BT, U.K.

Single amino acid substitutions within protein structures often manifest with clinical conditions in humans. The mutation of a single amino can significantly alter protein folding and stability, or change protein dynamics to influence function. The chemical engineering field has developed a large toolset for predicting the influence of point mutations with the aim of guiding the design of improved and more stable proteins. Read More

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Novel TNNT1 mutation and mild nemaline myopathy phenotype in an Italian patient.

Neuromuscul Disord 2021 Mar 6. Epub 2021 Mar 6.

UOC Neurofisiopatologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli 8, Rome 00168, Italy; Dipartimento Universitario di Neuroscienze, Università Cattolica del Sacro Cuore, Roma, Italy.

Mutations in the TNNT1 gene cause an infantile, lethal form of myopathy named "Amish" Nemaline Myopathy. Adult patients are very rarely described. We report a 49-year-old patient who presented a slowly progressive phenotype characterized by myalgia, exercise intolerance and dyspnea since infancy. Read More

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Biallelic hypomorphic mutations in HEATR5B, encoding HEAT repeat-containing protein 5B, in a neurological syndrome with pontocerebellar hypoplasia.

Eur J Hum Genet 2021 Apr 6. Epub 2021 Apr 6.

Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.

HEAT repeats are 37-47 amino acid flexible tandem repeat structural motifs occurring in a wide variety of eukaryotic proteins with diverse functions. Due to their ability to undergo elastic conformational changes, they often serve as scaffolds at sites of protein interactions. Here, we describe four affected children from two families presenting with pontocerebellar hypoplasia manifest clinically with neonatal seizures, severe intellectual disability, and motor delay. Read More

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Deficiency of TMEM53 causes a previously unknown sclerosing bone disorder by dysregulation of BMP-SMAD signaling.

Nat Commun 2021 04 6;12(1):2046. Epub 2021 Apr 6.

Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.

Bone formation represents a heritable trait regulated by many signals and complex mechanisms. Its abnormalities manifest themselves in various diseases, including sclerosing bone disorder (SBD). Exploration of genes that cause SBD has significantly improved our understanding of the mechanisms that regulate bone formation. Read More

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Wedding of Molecular Alterations and Immune Checkpoint Blockade: Genomics as a Matchmaker.

J Natl Cancer Inst 2021 Apr 6. Epub 2021 Apr 6.

The University of Texas MD Anderson Cancer Center, Department of Investigational Cancer Therapeutics, Houston, TX, USA.

The development of checkpoint blockade immunotherapy has transformed the medical oncology armamentarium. But, despite its favorable impact on clinical outcomes, immunotherapy benefits only a subset of patients, and a substantial proportion of these individuals eventually manifest resistance. Serious immune-related adverse events and hyper-progression have also been reported. Read More

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AON-based degradation of c.151C>T mutant transcripts associated with dominantly inherited hearing impairment DFNA9.

Mol Ther Nucleic Acids 2021 Jun 1;24:274-283. Epub 2021 Mar 1.

Department of Otorhinolaryngology, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.

The c.151C>T founder mutation in is a frequent cause of late-onset, dominantly inherited hearing impairment and vestibular dysfunction (DFNA9) in the Dutch/Belgian population. The initial clinical symptoms only manifest between the 3rd and 5th decade of life, which leaves ample time for therapeutic intervention. Read More

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A Common 3'UTR Variant of the Gene Is Associated With Infant Life-Threatening and Sudden Death Events in the Italian Population.

Front Neurol 2021 19;12:642735. Epub 2021 Mar 19.

Laboratorio di Genetica e Genomica delle Malattie Rare, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Giannina Gaslini, Genoa, Italy.

Heterozygous mutations in the Paired like homeobox 2b () gene are causative of congenital central hypoventilation syndrome (CCHS), a rare monogenic disorder belonging to the family of neurocristopathies and due to a defective development of the autonomic nervous system. Most patients manifest sudden symptoms within 1 year of birth, mainly represented by central apnea and cyanosis episodes. The sudden appearance of hypoxic manifestations in CCHS and their occurrence during sleep resemble two other unexplained perinatal disorders, apparent life-threatening event (ALTE) and sudden and unexpected infant death (SUID), among which the vast majority is represented by sudden infant death syndrome (SIDS). Read More

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Genetics of Acromegaly and Gigantism.

J Clin Med 2021 Mar 29;10(7). Epub 2021 Mar 29.

Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.

Growth hormone (GH)-secreting pituitary tumours represent the most genetically determined pituitary tumour type. This is true both for germline and somatic mutations. Germline mutations occur in several known genes (, , , , , , , ) as well as familial cases with currently unknown genes, while somatic mutations in are present in up to 40% of tumours. Read More

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[The value of genetic diagnosis of deafness in evaluating the prognosis of cochlear implantation].

Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 2021 Mar;35(3):274-281

Congenital deafness is known as the most common birth defect, and most sufferers from it manifest sensorineural hearing loss (SNHL), with hereditary factors responsible for approximately 60% of the cases of deafness. At present, cochlear implantation (CI) is regarded as the most mature and effective solution to treating severe and extremely severe SNHL. However, the outcome of implantation varies due to different genetic factors. Read More

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A novel de novo DDX3X missense variant in a female with brachycephaly and intellectual disability: a case report.

Ital J Pediatr 2021 Mar 31;47(1):81. Epub 2021 Mar 31.

Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.

Background: De novo pathogenic variants in the DDX3X gene are reported to account for 1-3% of unexplained intellectual disability (ID) in females, leading to the rare disease known as DDX3X syndrome (MRXSSB, OMIM #300958). Besides ID, these patients manifest a variable clinical presentation, which includes neurological and behavioral defects, and abnormal brain MRIs.

Case Presentation: We report a 10-year-old girl affected by delayed psychomotor development, delayed myelination, and polymicrogyria (PMG). Read More

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Modern diagnostic capabilities of neonatal screening for primary immunodeficiencies in newborns.

Clin Exp Pediatr 2021 Mar 25. Epub 2021 Mar 25.

Federal State Autonomous Educational Institution of Higher Education, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russia.

Population screening of newborns is an extremely important and informative diagnostic approach that allows early identification of babies who are predisposed to the development of a number of serious diseases. Some of these diseases are known and have effective treatment methods. Neonatal screening enables the early diagnosis and subsequent timely initiation of therapy. Read More

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Exome sequencing shines in empty follicle syndrome: zona pellucida gene mutations manifest genuine empty follicle syndrome.

Fertil Steril 2021 May 26;115(5):1170-1171. Epub 2021 Mar 26.

Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China (USTC), Anhui, China.

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Towards customized cancer vaccines: a promising filed in personalized cancer medicine.

Expert Rev Vaccines 2021 Apr 5:1-14. Epub 2021 Apr 5.

Department of Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital),Hangzhou City, China.

Introduction: Cancer remains a major source of disease burden worldwide. Although cancer vaccines have been developed, most currently available cancer vaccines have limited therapeutic efficacy. Recent research using novel sequencing and bioinformatic tools has led scientists to realize that each tumor harbors a unique set of genetic mutations that can manifest as tumor-specific neoantigens. Read More

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MicroRNA-34a: Potent Tumor Suppressor, Cancer Stem Cell Inhibitor, and Potential Anticancer Therapeutic.

Front Cell Dev Biol 2021 8;9:640587. Epub 2021 Mar 8.

Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States.

Overwhelming evidence indicates that virtually all treatment-naive tumors contain a subpopulation of cancer cells that possess some stem cell traits and properties and are operationally defined as cancer cell stem cells (CSCs). CSCs manifest inherent heterogeneity in that they may exist in an epithelial and proliferative state or a mesenchymal non-proliferative and invasive state. Spontaneous tumor progression, therapeutic treatments, and (epi)genetic mutations may also induce plasticity in non-CSCs and reprogram them into stem-like cancer cells. Read More

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A Rare Case of RYR2 Mutation Causing Sudden Cardiac Arrest Due to Catecholaminergic Polymorphic Ventricular Tachycardia.

Cureus 2021 Feb 18;13(2):e13417. Epub 2021 Feb 18.

Cardiology, Northwestern Medicine McHenry Hospital, McHenry, USA.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a complex disorder that can induce lethal ventricular arrhythmias, secondary to activation of the sympathetic nervous system. This disease is often diagnosed in childhood but can also manifest in adulthood (the early 40s). Gene mutations such as CALM1, RYR2 (ryanodine receptor-2), CASQ2, and TRDN have been identified as common causes of CPVT. Read More

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February 2021

EML4-ALK induces cellular senescence in mortal normal human cells and promotes anchorage-independent growth in hTERT-transduced normal human cells.

BMC Cancer 2021 Mar 24;21(1):310. Epub 2021 Mar 24.

Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Room 3068A, Bethesda, MD, 20892, USA.

Background: Chromosomal inversions involving anaplastic lymphoma kinase (ALK) and echinoderm microtubule associated protein like 4 (EML4) generate a fusion protein EML4-ALK in non-small cell lung cancer (NSCLC). The understanding of EML4-ALK function can be improved by a functional study using normal human cells.

Methods: Here we for the first time conduct such study to examine the effects of EML4-ALK on cell proliferation, cellular senescence, DNA damage, gene expression profiles and transformed phenotypes. Read More

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