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Mendelian disease

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https://www.readbyqxmd.com/read/28448979/combination-of-correctors-rescues-cftr-transmembrane-domain-mutants-by-mitigating-their-interactions-with-proteostasis
#1
Miquéias Lopes-Pacheco, Clément Boinot, Inna Sabirzhanova, Daniele Rapino, Liudmila Cebotaru
BACKGROUND/AIMS: Premature degradation of mutated cystic fibrosis transmembrane conductance regulator (CFTR) protein causes cystic fibrosis (CF), the commonest Mendelian disease in Caucasians. Despite recent advances in precision medicines for CF patients, many CFTR mutants have not been characterized and the effects of these new therapeutic approaches are still unclear for those mutants. METHODS: Cells transfected or stably expressing four CFTR transmembrane-domain mutants (G85E, E92K, L1077P, and M1101K) were used to: 1) characterize the mutants according to their protein expression, thermal sensitivity, and degradation pathways; 2) evaluate the effects of correctors in rescuing them; and 3) explore the effects of correctors on CFTR interactions with proteostasis components...
April 25, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28448539/causal-relationship-between-obesity-and-serum-testosterone-status-in-men-a-bi-directional-mendelian-randomization-analysis
#2
Joel Eriksson, Robin Haring, Niels Grarup, Liesbeth Vandenput, Henri Wallaschofski, Erik Lorentzen, Torben Hansen, Dan Mellström, Oluf Pedersen, Matthias Nauck, Mattias Lorentzon, Lise Lotte Nystrup Husemoen, Henry Völzke, Magnus Karlsson, Sebastian E Baumeister, Allan Linneberg, Claes Ohlsson
CONTEXT: Obesity in men is associated with low serum testosterone and both are associated with several diseases and increased mortality. OBJECTIVES: Examine the direction and causality of the relationship between body mass index (BMI) and serum testosterone. DESIGN: Bi-directional Mendelian randomization (MR) analysis on prospective cohorts. SETTING: Five cohorts from Denmark, Germany and Sweden (Inter99, SHIP, SHIP Trend, GOOD and MrOS Sweden)...
2017: PloS One
https://www.readbyqxmd.com/read/28446513/frequent-hypomorphic-alleles-account-for-a-significant-fraction-of-abca4-disease-and-distinguish-it-from-age-related-macular-degeneration
#3
Jana Zernant, Winston Lee, Frederick T Collison, Gerald A Fishman, Yuri V Sergeev, Kaspar Schuerch, Janet R Sparrow, Stephen H Tsang, Rando Allikmets
BACKGROUND: Variation in the ABCA4 gene is causal for, or associated with, a wide range of phenotypes from early onset Mendelian retinal dystrophies to late-onset complex disorders such as age-related macular degeneration (AMD). Despite substantial progress in determining the causal genetic variation, even complete sequencing of the entire open reading frame and splice sites of ABCA4 identifies biallelic mutations in only 60%-70% of cases; 20%-25% remain with one mutation and no mutations are found in 10%-15% of cases with clinically confirmed ABCA4 disease...
April 26, 2017: Journal of Medical Genetics
https://www.readbyqxmd.com/read/28444290/low-density-lipoproteins-cause-atherosclerotic-cardiovascular-disease-1-evidence-from-genetic-epidemiologic-and-clinical-studies-a-consensus-statement-from-the-european-atherosclerosis-society-consensus-panel
#4
Brian A Ference, Henry N Ginsberg, Ian Graham, Kausik K Ray, Chris J Packard, Eric Bruckert, Robert A Hegele, Ronald M Krauss, Frederick J Raal, Heribert Schunkert, Gerald F Watts, Jan Borén, Sergio Fazio, Jay D Horton, Luis Masana, Stephen J Nicholls, Børge G Nordestgaard, Bart van de Sluis, Marja-Riitta Taskinen, Lale Tokgözoglu, Ulf Landmesser, Ulrich Laufs, Olov Wiklund, Jane K Stock, M John Chapman, Alberico L Catapano
Aims: To appraise the clinical and genetic evidence that low-density lipoproteins (LDLs) cause atherosclerotic cardiovascular disease (ASCVD). Methods and results: We assessed whether the association between LDL and ASCVD fulfils the criteria for causality by evaluating the totality of evidence from genetic studies, prospective epidemiologic cohort studies, Mendelian randomization studies, and randomized trials of LDL-lowering therapies. In clinical studies, plasma LDL burden is usually estimated by determination of plasma LDL cholesterol level (LDL-C)...
April 24, 2017: European Heart Journal
https://www.readbyqxmd.com/read/28442717/the-biomarker-and-causal-roles-of-homoarginine-in-the-development-of-cardiometabolic-diseases-an-observational-and-mendelian-randomization-analysis
#5
Ilkka Seppälä, Niku Oksala, Antti Jula, Antti J Kangas, Pasi Soininen, Nina Hutri-Kähönen, Winfried März, Andreas Meinitzer, Markus Juonala, Mika Kähönen, Olli T Raitakari, Terho Lehtimäki
High L-homoarginine (hArg) levels are directly associated with several risk factors for cardiometabolic diseases whereas low levels predict increased mortality in prospective studies. The biomarker role of hArg in young adults remains unknown. To study the predictive value of hArg in the development of cardiometabolic risk factors and diseases, we utilized data on high-pressure liquid chromatography-measured hArg, cardiovascular risk factors, ultrasound markers of preclinical atherosclerosis and type 2 diabetes from the population-based Young Finns Study involving 2,106 young adults (54...
April 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28441826/-a-childhood-onset-rapid-onset-dystonia-parkinsonism-family-with-atp1a3-gene-mutation-and-literatures-review
#6
C L Zhang, F Yin, F He, N Gai, Z Q Shi, J Peng
Objective: To explore clinical characteristics, treatment, and prognosis of a family with childhood-onset rapid-onset dystonia parkinsonism (RDP) caused by ATP1A3 gene mutation and review literatures. Method: The clinical data of a RDP child, his brother and mother had been analyzed retrospectively. This family was admitted to Xiangya Hospital in January 2016. DNA samples were analyzed by the next-generation sequencing and confirmed by Sanger sequencing. Related literature from PubMed, Online Mendelian Inheritance in Man (OMIM), CNKI and Wanfang databases to date (up to October 2016) with"Rapid-onset dystonia-parkinsonism"RDP"DYT12" as key words was reviewed...
April 2, 2017: Zhonghua Er Ke za Zhi. Chinese Journal of Pediatrics
https://www.readbyqxmd.com/read/28439028/bgp-15-prevents-the-death-of-neurons-in-a-mouse-model-of-familial-dysautonomia
#7
Sarah B Ohlen, Magdalena L Russell, Michael J Brownstein, Frances Lefcort
Hereditary sensory and autonomic neuropathy type III, or familial dysautonomia [FD; Online Mendelian Inheritance in Man (OMIM) 223900], affects the development and long-term viability of neurons in the peripheral nervous system (PNS) and retina. FD is caused by a point mutation in the gene IKBKAP/ELP1 that results in a tissue-specific reduction of the IKAP/ELP1 protein, a subunit of the Elongator complex. Hallmarks of the disease include vasomotor and cardiovascular instability and diminished pain and temperature sensation caused by reductions in sensory and autonomic neurons...
April 24, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28438747/low-ldl-cholesterol-pcsk9-and-hmgcr-genetic-variation-and-risk-of-alzheimer-s-disease-and-parkinson-s-disease-mendelian-randomisation-study
#8
Marianne Benn, Børge G Nordestgaard, Ruth Frikke-Schmidt, Anne Tybjærg-Hansen
Objective To test the hypothesis that low density lipoprotein (LDL) cholesterol due to genetic variation in the genes responsible for LDL cholesterol metabolism and biosynthesis(PCSK9 and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), respectively) is associated with a high risk of Alzheimer's disease, vascular dementia, any dementia, and Parkinson's disease in the general population.Design Mendelian randomisation study.Setting Copenhagen General Population Study and Copenhagen City Heart Study.Participants 111 194 individuals from the Danish general population...
April 24, 2017: BMJ: British Medical Journal
https://www.readbyqxmd.com/read/28438488/whole-genome-sequencing-predicts-novel-human-disease-models-in-rhesus-macaques
#9
Benjamin N Bimber, Ranjani Ramakrishnan, Rita Cervera-Juanes, Ravi Madhira, Samuel M Peterson, Robert B Norgren, Betsy Ferguson
Rhesus macaques are an important pre-clinical model of human disease. To advance our understanding of genomic variation that may influence disease, we surveyed genome-wide variation in 21 rhesus macaques. We employed best-practice variant calling, validated with Mendelian inheritance. Next, we used alignment data from our cohort to detect genomic regions likely to produce inaccurate genotypes, potentially due to either gene duplication or structural variation between individuals. We generated a final dataset of >16 million high confidence variants, including 13 million in Chinese-origin rhesus macaques, an increasingly important disease model...
April 21, 2017: Genomics
https://www.readbyqxmd.com/read/28436984/genomic-analyses-identify-hundreds-of-variants-associated-with-age-at-menarche-and-support-a-role-for-puberty-timing-in-cancer-risk
#10
Felix R Day, Deborah J Thompson, Hannes Helgason, Daniel I Chasman, Hilary Finucane, Patrick Sulem, Katherine S Ruth, Sean Whalen, Abhishek K Sarkar, Eva Albrecht, Elisabeth Altmaier, Marzyeh Amini, Caterina M Barbieri, Thibaud Boutin, Archie Campbell, Ellen Demerath, Ayush Giri, Chunyan He, Jouke J Hottenga, Robert Karlsson, Ivana Kolcic, Po-Ru Loh, Kathryn L Lunetta, Massimo Mangino, Brumat Marco, George McMahon, Sarah E Medland, Ilja M Nolte, Raymond Noordam, Teresa Nutile, Lavinia Paternoster, Natalia Perjakova, Eleonora Porcu, Lynda M Rose, Katharina E Schraut, Ayellet V Segrè, Albert V Smith, Lisette Stolk, Alexander Teumer, Irene L Andrulis, Stefania Bandinelli, Matthias W Beckmann, Javier Benitez, Sven Bergmann, Murielle Bochud, Eric Boerwinkle, Stig E Bojesen, Manjeet K Bolla, Judith S Brand, Hiltrud Brauch, Hermann Brenner, Linda Broer, Thomas Brüning, Julie E Buring, Harry Campbell, Eulalia Catamo, Stephen Chanock, Georgia Chenevix-Trench, Tanguy Corre, Fergus J Couch, Diana L Cousminer, Angela Cox, Laura Crisponi, Kamila Czene, George Davey Smith, Eco J C N de Geus, Renée de Mutsert, Immaculata De Vivo, Joe Dennis, Peter Devilee, Isabel Dos-Santos-Silva, Alison M Dunning, Johan G Eriksson, Peter A Fasching, Lindsay Fernández-Rhodes, Luigi Ferrucci, Dieter Flesch-Janys, Lude Franke, Marike Gabrielson, Ilaria Gandin, Graham G Giles, Harald Grallert, Daniel F Gudbjartsson, Pascal Guénel, Per Hall, Emily Hallberg, Ute Hamann, Tamara B Harris, Catharina A Hartman, Gerardo Heiss, Maartje J Hooning, John L Hopper, Frank Hu, David J Hunter, M Arfan Ikram, Hae Kyung Im, Marjo-Riitta Järvelin, Peter K Joshi, David Karasik, Manolis Kellis, Zoltan Kutalik, Genevieve LaChance, Diether Lambrechts, Claudia Langenberg, Lenore J Launer, Joop S E Laven, Stefania Lenarduzzi, Jingmei Li, Penelope A Lind, Sara Lindstrom, YongMei Liu, Jian'an Luan, Reedik Mägi, Arto Mannermaa, Hamdi Mbarek, Mark I McCarthy, Christa Meisinger, Thomas Meitinger, Cristina Menni, Andres Metspalu, Kyriaki Michailidou, Lili Milani, Roger L Milne, Grant W Montgomery, Anna M Mulligan, Mike A Nalls, Pau Navarro, Heli Nevanlinna, Dale R Nyholt, Albertine J Oldehinkel, Tracy A O'Mara, Sandosh Padmanabhan, Aarno Palotie, Nancy Pedersen, Annette Peters, Julian Peto, Paul D P Pharoah, Anneli Pouta, Paolo Radice, Iffat Rahman, Susan M Ring, Antonietta Robino, Frits R Rosendaal, Igor Rudan, Rico Rueedi, Daniela Ruggiero, Cinzia F Sala, Marjanka K Schmidt, Robert A Scott, Mitul Shah, Rossella Sorice, Melissa C Southey, Ulla Sovio, Meir Stampfer, Maristella Steri, Konstantin Strauch, Toshiko Tanaka, Emmi Tikkanen, Nicholas J Timpson, Michela Traglia, Thérèse Truong, Jonathan P Tyrer, André G Uitterlinden, Digna R Velez Edwards, Veronique Vitart, Uwe Völker, Peter Vollenweider, Qin Wang, Elisabeth Widen, Ko Willems van Dijk, Gonneke Willemsen, Robert Winqvist, Bruce H R Wolffenbuttel, Jing Hua Zhao, Magdalena Zoledziewska, Marek Zygmunt, Behrooz Z Alizadeh, Dorret I Boomsma, Marina Ciullo, Francesco Cucca, Tõnu Esko, Nora Franceschini, Christian Gieger, Vilmundur Gudnason, Caroline Hayward, Peter Kraft, Debbie A Lawlor, Patrik K E Magnusson, Nicholas G Martin, Dennis O Mook-Kanamori, Ellen A Nohr, Ozren Polasek, David Porteous, Alkes L Price, Paul M Ridker, Harold Snieder, Tim D Spector, Doris Stöckl, Daniela Toniolo, Sheila Ulivi, Jenny A Visser, Henry Völzke, Nicholas J Wareham, James F Wilson, Amanda B Spurdle, Unnur Thorsteindottir, Katherine S Pollard, Douglas F Easton, Joyce Y Tung, Jenny Chang-Claude, David Hinds, Anna Murray, Joanne M Murabito, Kari Stefansson, Ken K Ong, John R B Perry
The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to ∼370,000 women, we identify 389 independent signals (P < 5 × 10(-8)) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ∼7.4% of the population variance in age at menarche, corresponding to ∼25% of the estimated heritability. We implicate ∼250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues...
April 24, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28424468/effect-of-handgrip-on-coronary-artery-disease-and-myocardial-infarction-a-mendelian-randomization-study
#11
Lin Xu, Yuan Tao Hao
Observational studies have reported an association of handgrip strength with risk of cardiovascular disease. However, residual confounding and reverse causation may have influenced these findings. A Mendelian randomization (MR) study was conducted to examine whether handgrip is causally associated with cardiovascular disease. Two single nucleotide polymorphisms (SNPs), rs3121278 and rs752045, were used as the genetic instruments for handgrip. The effect of each SNP on coronary artery disease/myocardial infarction (CAD/MI) was weighted by its effect on handgrip strength, and estimates were pooled to provide a summary measure for the effect of increased handgrip on risk of CAD/MI...
April 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28424332/improving-genetic-diagnosis-in-mendelian-disease-with-transcriptome-sequencing
#12
Beryl B Cummings, Jamie L Marshall, Taru Tukiainen, Monkol Lek, Sandra Donkervoort, A Reghan Foley, Veronique Bolduc, Leigh B Waddell, Sarah A Sandaradura, Gina L O'Grady, Elicia Estrella, Hemakumar M Reddy, Fengmei Zhao, Ben Weisburd, Konrad J Karczewski, Anne H O'Donnell-Luria, Daniel Birnbaum, Anna Sarkozy, Ying Hu, Hernan Gonorazky, Kristl Claeys, Himanshu Joshi, Adam Bournazos, Emily C Oates, Roula Ghaoui, Mark R Davis, Nigel G Laing, Ana Topf, Peter B Kang, Alan H Beggs, Kathryn N North, Volker Straub, James J Dowling, Francesco Muntoni, Nigel F Clarke, Sandra T Cooper, Carsten G Bönnemann, Daniel G MacArthur
Exome and whole-genome sequencing are becoming increasingly routine approaches in Mendelian disease diagnosis. Despite their success, the current diagnostic rate for genomic analyses across a variety of rare diseases is approximately 25 to 50%. We explore the utility of transcriptome sequencing [RNA sequencing (RNA-seq)] as a complementary diagnostic tool in a cohort of 50 patients with genetically undiagnosed rare muscle disorders. We describe an integrated approach to analyze patient muscle RNA-seq, leveraging an analysis framework focused on the detection of transcript-level changes that are unique to the patient compared to more than 180 control skeletal muscle samples...
April 19, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28421071/monogenic-autoinflammatory-diseases-with-mendelian-inheritance-genes-mutations-and-genotype-phenotype-correlations
#13
REVIEW
Davide Martorana, Francesco Bonatti, Paola Mozzoni, Augusto Vaglio, Antonio Percesepe
Autoinflammatory diseases (AIDs) are a genetically heterogeneous group of diseases caused by mutations of genes encoding proteins, which play a pivotal role in the regulation of the inflammatory response. In the pathogenesis of AIDs, the role of the genetic background is triggered by environmental factors through the modulation of the innate immune system. Monogenic AIDs are characterized by Mendelian inheritance and are caused by highly penetrant genetic variants in single genes. During the last years, remarkable progress has been made in the identification of disease-associated genes by using new technologies, such as next-generation sequencing, which has allowed the genetic characterization in undiagnosed patients and in sporadic cases by means of targeted resequencing of a gene panel and whole exome sequencing...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28420927/in-silico-analysis-of-fragile-histidine-triad-involved-in-regression-of-carcinoma
#14
Muhammad Asif Rasheed, Fatima Tariq, Sara Afzal, Shazia Mannanv
Hepatocellular carcinoma (HCCa) is a primary malignancy of the liver. Many different proteins are involved in HCCa including insulin growth factor (IGF) II , signal transducers and activators of transcription (STAT) 3, STAT4, mothers against decapentaplegic homolog 4 (SMAD 4), fragile histidine triad (FHIT) and selective internal radiation therapy (SIRT) etc. The present study is based on the bioinformatics analysis of FHIT protein in order to understand the proteomics aspect and improvement of the diagnosis of the disease based on the protein...
April 2017: JPMA. the Journal of the Pakistan Medical Association
https://www.readbyqxmd.com/read/28419997/examining-the-causal-role-of-leptin-in-alzheimer-s-disease-a-mendelian-randomization-study
#15
Matthew L Romo, C Mary Schooling
No abstract text is available yet for this article.
April 19, 2017: Neuroendocrinology
https://www.readbyqxmd.com/read/28418605/the-g534e-variant-in-habp2-is-not-associated-with-increased-risk-of-familial-nonmedullary-thyroid-cancer-in-brazilian-kindreds
#16
Luis Eduardo Barbalho de Mello, Aline Neves Araujo, Camila Xavier Alves, Fernando José de Pinto Paiva, José Brandão-Neto, Janete M Cerutti
Familial nonmedullary thyroid cancer (FNMTC) encompasses a heterogeneous group of diseases that includes both syndromic and nonsyndromic associated tumours. The syndromic group is characterized by a preponderance of nonthyroidal tumours and is associated with Mendelian cancer syndromes. Nonsyndromic groups, which account for 95% of the cases, are characterized by a significantly increased rate of benign or malignant thyroid tumours of follicular-cell origin in the same family and are not associated with other Mendelian cancer syndromes...
April 18, 2017: Clinical Endocrinology
https://www.readbyqxmd.com/read/28415856/gene-and-variant-annotation-for-mendelian-disorders-in-the-era-of-advanced-sequencing-technologies
#17
Samya Chakravorty, Madhuri Hegde
Comprehensive annotations of genetic and noncoding regions and corresponding accurate variant classification for Mendelian diseases are the next big challenge in the new genomic era of personalized medicine. Progress in the development of faster and more accurate pipelines for genome annotation and variant classification will lead to the discovery of more novel disease associations and candidate therapeutic targets. This ultimately will facilitate better patient recruitment in clinical trials. In this review, we describe the trends in research at the intersection of basic and clinical genomics that aims to increase understanding of overall genomic complexity, complex inheritance patterns of disease, and patient-phenotype-specific genomic associations...
April 17, 2017: Annual Review of Genomics and Human Genetics
https://www.readbyqxmd.com/read/28413711/high-throughput-sequencing-revealed-a-novel-setx-mutation-in-a-hungarian-patient-with-amyotrophic-lateral-sclerosis
#18
Kornélia Tripolszki, Dóra Török, David Goudenège, Katalin Farkas, Adrienn Sulák, Nóra Török, József I Engelhardt, Péter Klivényi, Vincent Procaccio, Nikoletta Nagy, Márta Széll
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the degeneration of the motor neurons. To date, 126 genes have been implicated in ALS. Therefore, the heterogenous genetic background of ALS requires comprehensive genetic investigative approaches. METHODS: In this study, DNA from 28 Hungarian ALS patients was subjected to targeted high-throughput sequencing of the coding regions of three Mendelian ALS genes: FUS, SETX, and C9ORF72...
April 2017: Brain and Behavior
https://www.readbyqxmd.com/read/28412959/opportunities-for-developing-therapies-for-rare-genetic-diseases-focus-on-gain-of-function-and-allostery
#19
Binbin Chen, Russ B Altman
BACKGROUND: Advances in next generation sequencing technologies have revolutionized our ability to discover the causes of rare genetic diseases. However, developing treatments for these diseases remains challenging. In fact, when we systematically analyze the US FDA orphan drug list, we find that only 8% of rare diseases have an FDA-designated drug. Our approach leverages three primary insights: first, diseases with gain-of-function mutations and late onset are more likely to have drug options; second, drugs are more often inhibitors than activators; and third, some disease-causing proteins can be rescued by allosteric activators in diseases due to loss-of-function mutations...
April 17, 2017: Orphanet Journal of Rare Diseases
https://www.readbyqxmd.com/read/28411893/genomic-approaches-to-hypertension
#20
REVIEW
Sheriff N Dodoo, Ivor J Benjamin
Genomic insights and analyses of Mendelian hypertension (HTN) syndromes and Genome-Wide Association study (GWAS) on essential hypertension have contributed to the depth of understanding of the genetics origins of hypertension. Mendelian syndromes are important for the field, since such knowledge leads to specific insights about disease pathogenesis and the potential for precision medicine. The clinical impact of findings of on essential hypertension is continuously evolving, and the insights accrued will refine efforts to combat the societal impact of hypertension...
May 2017: Cardiology Clinics
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