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https://www.readbyqxmd.com/read/29161432/modeling-mutant-wild-type-interactions-to-ascertain-pathogenicity-of-prokr2-missense-variants-in-patients-with-isolated-gnrh-deficiency
#1
Kimberly H Cox, Luciana M B Oliveira, Lacey Plummer, Braden Corbin, Thomas Gardella, Ravikumar Balasubramanian, William F Crowley
A major challenge in human genetics is the validation of pathogenicity of heterozygous missense variants. This problem is well-illustrated by PROKR2 variants associated with Isolated GnRH Deficiency (IGD). Homozygous, loss of function variants in PROKR2 were initially implicated in autosomal recessive IGD; however, most IGD-associated PROKR2 variants are heterozygous. Moreover, while IGD patient cohorts are enriched for PROKR2 missense variants similar rare variants are also found in normal individuals. To elucidate the pathogenic mechanisms distinguishing IGD-associated PROKR2 variants from rare variants in controls, we assessed 59 variants using three approaches: (i) in silico prediction, (ii) traditional in vitro functional assays across 3 signaling pathways with mutant-alone transfections, and (iii) modified in vitro assays with mutant and wild-type expression constructs co-transfected to model in vivo heterozygosity...
November 17, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/29161300/brca1-and-brca2-mutational-profile-and-prevalence-in-hereditary-breast-and-ovarian-cancer-hboc-probands-from-southern-brazil-are-international-testing-criteria-appropriate-for-this-specific-population
#2
Bárbara Alemar, Cleandra Gregório, Josef Herzog, Camila Matzenbacher Bittar, Cristina Brinckmann Oliveira Netto, Osvaldo Artigalas, Ida Vanessa D Schwartz, Jordy Coffa, Suzi Alves Camey, Jeffrey Weitzel, Patricia Ashton-Prolla
BACKGROUND: Germline pathogenic variants in BRCA1 and BRCA2 (BRCA) are the main cause of Hereditary Breast and Ovarian Cancer syndrome (HBOC). METHODS: In this study we evaluated the mutational profile and prevalence of BRCA pathogenic/likely pathogenic variants among probands fulfilling the NCCN HBOC testing criteria. We characterized the clinical profile of these individuals and explored the performance of international testing criteria. RESULTS: A pathogenic/likely pathogenic variant was detected in 19...
2017: PloS One
https://www.readbyqxmd.com/read/29160310/cyclin-d-cdk4-kinase-destabilizes-pd-l1-via-cul3-spop-to-control-cancer-immune-surveillance
#3
Jinfang Zhang, Xia Bu, Haizhen Wang, Yasheng Zhu, Yan Geng, Naoe Taira Nihira, Yuyong Tan, Yanpeng Ci, Fei Wu, Xiangpeng Dai, Jianping Guo, Yu-Han Huang, Caoqi Fan, Shancheng Ren, Yinghao Sun, Gordon J Freeman, Piotr Sicinski, Wenyi Wei
Treatments that target immune checkpoints, such as the one mediated by programmed cell death protein 1 (PD-1) and its ligand PD-L1, have been approved for treating human cancers with durable clinical benefit(1,2). However, many cancer patients fail to respond to anti-PD-1/PD-L1 treatment, and the underlying mechanism(s) is not well understood(3-5). Recent studies revealed that response to PD-1/PD-L1 blockade might correlate with PD-L1 expression levels in tumor cells(6,7). Hence, it is important to mechanistically understand the pathways controlling PD-L1 protein expression and stability, which can offer a molecular basis to improve the clinical response rate and efficacy of PD-1/PD-L1 blockade in cancer patients...
November 16, 2017: Nature
https://www.readbyqxmd.com/read/29160033/discordant-fetal-phenotype-of-hypophosphatasia-in-two-siblings
#4
Satoru Ikenoue, Kei Miyakoshi, Tomohiro Ishii, Yu Sato, Toshimitsu Otani, Yohei Akiba, Yoshifumi Kasuga, Daigo Ochiai, Tadashi Matsumoto, Yosuke Ichihashi, Yohei Matsuzaki, Kanako Tachikawa, Toshimi Michigami, Gen Nishimura, Kazushige Ikeda, Tomonobu Hasegawa, Mamoru Tanaka
Hypophosphatasia (HPP) is an autosomal recessive metabolic disorder with impaired bone mineralization due to mutations in the ALPL gene. The genotype-phenotype correlation of this disorder has been widely described. Here, we present two affected siblings, whose fetal phenotypes were discordant. A 31-year-old Japanese woman, G0P0, was referred to our institution because of fetal micromelia. After obstetric counseling, the pregnancy was terminated at 21 weeks' gestation. Post-mortem radiographs demonstrated severely defective mineralization of the skeleton...
November 21, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/29160006/kaufman-oculocerebrofacial-syndrome-novel-ube3b-mutations-and-clinical-features-in-four-unrelated-patients
#5
Rüstem Yilmaz, Katalin Szakszon, Anna Altmann, Umut Altunoglu, Leyli Senturk, Marianne McGuire, Olga Calabrese, Suneeta Madan-Khetarpal, Lina Basel-Vanagaite, Guntram Borck
The "blepharophimosis-mental retardation" syndromes (BMRS) consist of a group of clinically and genetically heterogeneous congenital malformation syndromes, where short palpebral fissures and intellectual disability associate with a distinct set of other morphological features. Kaufman oculocerebrofacial syndrome represents a rare and recently reevaluated entity within the BMR syndromes and is caused by biallelic mutations of UBE3B. Affected individuals typically show microcephaly, impaired somatic growth, gastrointestinal and genitourinary problems, ectodermal anomalies and a characteristic face with short, upslanted palpebral fissures, depressed nasal bridge...
November 21, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/29159890/whole-exome-sequencing-reveals-a-mutation-in-armc9-as-a-cause-of-mental-retardation-ptosis-and-polydactyly
#6
Anjana Kar, Shubha R Phadke, Aneek Das Bhowmik, Ashwin Dalal
Intellectual disability (ID) refers to deficits in mental abilities, social behavior, and motor skills to perform activities of daily living as compared to peers. Numerous genetic and environmental factors may be responsible for ID. We report on elucidation of molecular basis for syndromic ID associated with ptosis, polydactyly, and MRI features suggestive of Joubert syndrome using homozygosity mapping followed by exome sequencing. The analysis revealed a novel synonymous variation p.T293T (c.879G>A) which leads to a splicing defect in ARMC9 gene...
November 21, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/29159868/tarsal-carpal-coalition-syndrome-report-of-a-novel-missense-mutation-in-nog-gene-and-phenotypic-delineation
#7
Aneek Das Bhowmik, Vijayalakshmi Salem Ramakumaran, Ashwin Dalal
We report a family of Indian origin presenting with Tarsal-carpal coalition syndrome (TCC), which is a rare genetic disorder of skeletal abnormalities, inherited in autosomal dominant manner. In this family, three individuals (mother and two children) were found to be similarly affected with slight intrafamilial individual variability in the phenotype. Sanger sequencing revealed a novel heterozygous missense mutation in NOG gene (NM_005450.4:c.611G>A) in all the affected individuals of the family. Until now only six mutations have been reported in different families affected with TCC syndrome worldwide...
November 21, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/29159838/eys-mutation-update-in-silico-assessment-of-271-reported-and-26-novel-variants-in-patients-with-retinitis-pigmentosa
#8
Muriël Messchaert, Lonneke Haer-Wigman, Muhammad I Khan, Frans P M Cremers, Rob W J Collin
Mutations in Eyes shut homolog (EYS) are one of the most common causes of autosomal recessive (ar) retinitis pigmentosa (RP), a progressive blinding disorder. The exact function of the EYS protein and the pathogenic mechanisms underlying EYS-associated RP are still poorly understood, which hampers the interpretation of the causality of many EYS variants discovered to date. We collected all reported EYS variants present in 377 arRP index cases published before June 2017, and uploaded them in the Leiden Open Variation Database (www...
November 21, 2017: Human Mutation
https://www.readbyqxmd.com/read/29159459/epg5-related-vici-syndrome-a-primary-defect-of-autophagic-regulation-with-an-emerging-phenotype-overlapping-with-mitochondrial-disorders
#9
Shanti Balasubramaniam, Lisa G Riley, Anand Vasudevan, Mark J Cowley, Velimir Gayevskiy, Carolyn M Sue, Caitlin Edwards, Edward Edkins, Reimar Junckerstorff, C Kiraly-Borri, P Rowe, J Christodoulou
Vici syndrome is a rare, under-recognised, relentlessly progressive congenital multisystem disorder characterised by five principal features of callosal agenesis, cataracts, cardiomyopathy, combined immunodeficiency and oculocutaneous hypopigmentation. In addition, three equally consistent features (profound developmental delay, progressive failure to thrive and acquired microcephaly) are highly supportive of the diagnosis. Since its recognition as a distinct entity in 1988, an extended phenotype with sensorineural hearing loss, skeletal myopathy and variable involvement of virtually any organ system, including the lungs, thyroid, liver and kidneys, have been described...
November 21, 2017: JIMD Reports
https://www.readbyqxmd.com/read/29158924/methylmalonic-acidemia-with-novel-mut-gene-mutations
#10
Inusha Panigrahi, Savita Bhunwal, Harish Varma, Simranjeet Singh
A 5-year-old boy presented with recurrent episodes of fever, feeding problems, lethargy, from the age of 11 months, and poor weight gain. He was admitted and evaluated for metabolic causes and diagnosed as having methylmalonic acidemia (MMA). He was treated with vit B12 and carnitine supplements and has been on follow-up for the last 3 years. Mutation analysis by next generation sequencing (NGS), supplemented with Sanger sequencing, revealed two novel variants in the MUT gene responsible for MMA in exon 5 and exon 3, respectively...
2017: Case Reports in Genetics
https://www.readbyqxmd.com/read/29158875/a-gene-module-based-eqtl-analysis-prioritizing-disease-genes-and-pathways-in-kidney-cancer
#11
Mary Qu Yang, Dan Li, William Yang, Yifan Zhang, Jun Liu, Weida Tong
Clear cell renal cell carcinoma (ccRCC) is the most common and most aggressive form of renal cell cancer (RCC). The incidence of RCC has increased steadily in recent years. The pathogenesis of renal cell cancer remains poorly understood. Many of the tumor suppressor genes, oncogenes, and dysregulated pathways in ccRCC need to be revealed for improvement of the overall clinical outlook of the disease. Here, we developed a systems biology approach to prioritize the somatic mutated genes that lead to dysregulation of pathways in ccRCC...
2017: Computational and Structural Biotechnology Journal
https://www.readbyqxmd.com/read/29158767/screening-of-shox-gene-sequence-variants-in-saudi-arabian-children-with-idiopathic-short-stature
#12
Abdulla A Alharthi, Ehab I El-Hallous, Iman M Talaat, Hamed A Alghamdi, Matar I Almalki, Ahmed Gaber
Purpose: Short stature affects approximately 2%-3% of children, representing one of the most frequent disorders for which clinical attention is sought during childhood. Despite assumed genetic heterogeneity, mutations or deletions in the short stature homeobox-containing gene (SHOX) are frequently detected in subjects with short stature. Idiopathic short stature (ISS) refers to patients with short stature for various unknown reasons. The goal of this study was to screen all the exons of SHOX to identify related mutations...
October 2017: Korean Journal of Pediatrics
https://www.readbyqxmd.com/read/29158687/novel-mutation-of-fkbp10-in-a-pediatric-patient-with-osteogenesis-imperfecta-type-xi-identified-by-clinical-exome-sequencing
#13
Harvy Mauricio Velasco, Jessica L Morales
Osteogenesis imperfecta (OI) is a hereditary disease characterized by bone fragility caused by mutations in the proteins that support the formation of the extracellular matrix in the bone. The diagnosis of OI begins with clinical suspicion, from phenotypic findings at birth, low-impact fractures during childhood or family history that may lead to it. However, the variability in the semiology of the disease does not allow establishing an early diagnosis in all cases, and unfortunately, specific clinical data provided by the literature only report 28 patients with OI type XI...
2017: Application of Clinical Genetics
https://www.readbyqxmd.com/read/29158641/development-of-an-efficient-and-reproducible-regeneration-system-in-wheat-triticum-aestivum-l
#14
Rakesh Kumar, Harohalli Masthigowda Mamrutha, Amandeep Kaur, Karnam Venkatesh, Anita Grewal, Raj Kumar, Vinod Tiwari
The availability of reproducible regeneration system through tissue culture is a major bottleneck in wheat improvement program. The present study has considered to develop an efficient callus induction and regeneration system using mature and immature embryos as explants in recently released agronomically superior spring wheat varieties. An efficient sterilization process was standardized using 0.1% HgCl2 and 70% ethanol for both seeds and embryos. The maximum possible combinations of plant growth regulators (PGRs) were evaluated for their effect on different wheat regeneration processes through tissue culture starting from callus to root induction...
October 2017: Physiology and Molecular Biology of Plants: An International Journal of Functional Plant Biology
https://www.readbyqxmd.com/read/29158591/surgical-oncology-for-gliomas-the-state-of-the-art
#15
REVIEW
Nader Sanai, Mitchel S Berger
Surgical resection remains the mainstay of treatment for patients with glioma of any grade. Maximal resection of the tumour is central to achieving long-term disease control; however, the relationship between the extent of glioma resection and actual clinical benefit for the patient is predicated on the balance between cytoreduction and neurological morbidity. For the neurosurgical oncologist, the clinical rationale for undertaking increasingly extensive resections has gained traction. In parallel, novel surgical techniques and technologies have been developed that help improve patient outcomes...
November 21, 2017: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/29158418/a-novel-pkhd1-mutation-interacts-with-the-nonobese-1diabetic-genetic-background-to-cause-autoimmune-cholangitis
#16
Wenting Huang, Daniel B Rainbow, Yuehong Wu, David Adams, Pranavkumar Shivakumar, Leah Kottyan, Rebekah Karns, Bruce Aronow, Jorge Bezerra, M Eric Gershwin, Laurence B Peterson, Linda S Wicker, William M Ridgway
We previously reported that NOD.c3c4 mice develop spontaneous autoimmune biliary disease (ABD) with anti-mitochondrial Abs, histopathological lesions, and autoimmune T lymphocytes similar to human primary biliary cholangitis. In this article, we demonstrate that ABD in NOD.c3c4 and related NOD ABD strains is caused by a chromosome 1 region that includes a novel mutation in polycystic kidney and hepatic disease 1 (Pkhd1). We show that a long terminal repeat element inserted into intron 35 exposes an alternative polyadenylation site, resulting in a truncated Pkhd1 transcript...
November 20, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29158360/chromatin-modifying-gene-mutations-in-follicular-lymphoma
#17
Michael R Green
Follicular lymphoma (FL) is an indolent malignancy of germinal center B (GCB)-cells. Although the overall survival of FL patients has recently improved with the introduction of novel therapies, there is significant heterogeneity in patient outcome and a need for rationally designed therapeutic strategies that target disease biology. Next generation sequencing studies have identified chromatin modifying gene (CMG) mutations as a hallmark of FL, highlighting epigenetic modifiers as an attractive therapeutic target in this disease...
November 20, 2017: Blood
https://www.readbyqxmd.com/read/29158345/stable-oxidative-cytosine-modifications-accumulate-in-cardiac-mesenchymal-cells-from-type2-diabetes-patients-rescue-by-alpha-ketoglutarate-and-tet-tdg-functional-reactivation
#18
Francesco Spallotta, Chiara Cencioni, Sandra Atlante, Davide Garella, Mattia Cocco, Mattia Mori, Raffaella Mastrocola, Carsten Künne, Stefan Günther, Simona Nanni, Valerio Azzimato, Sven Zukunft, Angela Kornberger, Duran Sueruen, Frank Schnutgen, Harald von Melchner, Antonella Di Stilo, Manuela Aragno, Maarten Braspenning, Wim Van Criekinge, Miles J De Blasio, Rebecca H Ritchie, Germana Zaccagnini, Fabio Martelli, Antonella Farsetti, Ingrid Fleming, Thomas Braun, Andres Beiras-Fernandez, Bruno Botta, Massimo Collino, Massimo Bertinaria, Andreas M Zeiher, Carlo Gaetano
Rationale: Human cardiac mesenchymal cells (CMSCs) are a therapeutically-relevant primary cell population. Diabetes compromises CMSC function as consequence of metabolic alterations and incorporation of stable epigenetic changes. Objective: To investigate the role of α-ketoglutarate (αKG) in the epi-metabolic control of DNA demethylation in CMSCs. Methods and Results: Quantitative global analysis, methylated and hydroxymethylated DNA sequencing and gene specific GC methylation detection revealed an accumulation of 5mC, 5hmC and 5fC in the genomic DNA of human CMSCs isolated from diabetic (D) donors (D-CMSCs)...
November 20, 2017: Circulation Research
https://www.readbyqxmd.com/read/29158242/mutations-in-sugar-nucleotide-synthesis-genes-restore-holdfast-polysaccharide-anchoring-to-caulobacter-crescentus-holdfast-anchor-mutants
#19
Gail G Hardy, Evelyn Toh, Cécile Berne, Yves V Brun
Attachment is essential for microorganisms to establish interactions with both biotic and abiotic surfaces. Stable attachment of Caulobacter crescentus to surfaces requires an adhesive polysaccharide holdfast, but the exact composition of holdfast is unknown. The holdfast is anchored to the cell envelope by outer membrane proteins HfaA, HfaB and HfaD. Holdfast anchor gene mutations result in holdfast shedding and reduced cell adherence. Translocation of HfaA and HfaD to the cell surface requires HfaB. The Wzx homolog, HfsF, is predicted to be a bacterial polysaccharide flippase...
November 20, 2017: Journal of Bacteriology
https://www.readbyqxmd.com/read/29158240/novel-genes-and-regulators-that-influence-production-of-cell-surface-exopolysaccharides-in-sinorhizobium-meliloti
#20
Melanie J Barnett, Sharon R Long
Sinorhizobium meliloti is a soil-dwelling α-proteobacterium that engages in a nitrogen-fixing root nodule symbiosis with leguminous plants. Cell surface polysaccharides are important for both adapting to stresses in the soil and development of an effective symbiotic interaction. Among the polysaccharides characterized to date, the acidic exopolysaccharides EPS-I (succinoglycan) and EPS-II (galactoglucan) are particularly important for protection from abiotic stresses, biofilm formation, root colonization, and infection of plant roots...
November 20, 2017: Journal of Bacteriology
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