Article
Genetics & Heredity
Michele Brischigliaro, Elena Frigo, Samantha Corra, Cristiano De Pitta, Ildiko Szabo, Massimo Zeviani, Rodolfo Costa
Summary: Mutations in BCS1L are a common cause of human mitochondrial disease related to complex III deficiency, with diverse clinical symptoms and multisystem involvement. Studying genetic manipulation of Bcs1 in fruit flies reveals its fundamental role in complex III biogenesis and offers novel models for BCS1L-related human mitochondrial diseases.
JOURNAL OF MOLECULAR MEDICINE-JMM
(2021)
Article
Clinical Neurology
Omar Hikmat, Pirjo Isohanni, Nandaki Keshavan, Matteo P. Ferla, Elisa Fassone, Mary-Alice Abbott, Marcello Bellusci, Niklas Darin, David Dimmock, Daniele Ghezzi, Henry Houlden, Federica Invernizzi, Nazreen B. Kamarus Jaman, Manju A. Kurian, Eva Morava, Karin Naess, Juan Dario Ortigoza-Escobar, Sumit Parikh, Alessandra Pennisi, Giulia Barcia, Karin B. Tylleskar, Damien Brackman, Saskia B. Wortmann, Jenny C. Taylor, Laurence A. Bindoff, Vineta Fellman, Shamima Rahman
Summary: This study delineates the full phenotypic spectrum of BCS1L-related disease, identifies the correlations between age of onset, specific variants, and clinical manifestations, and associates early presentation with poor prognosis. The presence of the c.232A>G (p.Ser78Gly) variant is significantly linked to worse survival outcomes, while other pathogenic BCS1L variants are more common in patients with later symptom onset.
ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY
(2021)
Article
Multidisciplinary Sciences
Mark Bustoros, Shankara Anand, Romanos Sklavenitis-Pistofidis, Robert Redd, Eileen M. Boyle, Benny Zhitomirsky, Andrew J. Dunford, Yu-Tzu Tai, Selina J. Chavda, Cody Boehner, Carl Jannes Neuse, Mahshid Rahmat, Ankit Dutta, Tineke Casneuf, Raluca Verona, Efstathis Kastritis, Lorenzo Trippa, Chip Stewart, Brian A. Walker, Faith E. Davies, Meletios-Athanasios Dimopoulos, P. Leif Bergsagel, Kwee Yong, Gareth J. Morgan, Francois Aguet, Gad Getz, Irene M. Ghobrial
Summary: This study identifies six distinct molecular and clinical subtypes of smoldering multiple myeloma (SMM) using genetic alterations analysis. Three of these subtypes are associated with an increased risk of progression to active multiple myeloma.
NATURE COMMUNICATIONS
(2022)
Article
Cell Biology
Aurora Gomez-Vecino, Roberto Corchado-Cobos, Adrian Blanco-Gomez, Natalia Garcia-Sancha, Sonia Castillo-Lluva, Ana Martin-Garcia, Marina Mendiburu-Elicabe, Carlos Prieto, Sara Ruiz-Pinto, Guillermo Pita, Alejandro Velasco-Ruiz, Carmen Patino-Alonso, Purificacion Galindo-Villardon, Maria Linarejos Vera-Pedrosa, Jose Jalife, Jian-Hua Mao, Guillermo Macias de Plasencia, Andres Castellanos-Martin, Maria del Mar Saez-Freire, Susana Fraile-Martin, Telmo Rodrigues-Teixeira, Carmen Garcia-Macias, Julie Milena Galvis-Jimenez, Asuncion Garcia-Sanchez, Maria Isidoro-Garcia, Manuel Fuentes, Maria Begona Garcia-Cenador, Francisco Javier Garcia-Criado, Juan Luis Garcia-Hernandez, Maria Angeles Hernandez-Garcia, Juan Jesus Cruz-Hernandez, Cesar Augusto Rodriguez-Sanchez, Alejandro Martin Garcia-Sancho, Estefania Perez-Lopez, Antonio Perez-Martinez, Federico Gutierrez-Larraya, Antonio J. Carton, Jose Angel Garcia-Saenz, Ana Patino-Garcia, Miguel Martin, Teresa Alonso-Gordoa, Christof Vulsteke, Lieselot Croes, Sigrid Hatse, Thomas Van Brussel, Diether Lambrechts, Hans Wildiers, Hang Chang, Marina Holgado-Madruga, Anna Gonzalez-Neira, Pedro L. Sanchez, Jesu Perez Losada
Summary: Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, and identifying individuals at risk is challenging. In this study, the authors investigated intermediate molecular phenotypes (IMPs) associated with myocardial damage to determine CDA susceptibility. By analyzing a mouse cohort treated with doxorubicin and docetaxel, they identified genetic markers linked to IMPs and CDA. These markers were also found to be associated with CDA in cancer patients, highlighting their potential as predictive factors. Additionally, genetic risk scores were generated using machine-learning regression to personalize patient management.
Article
Genetics & Heredity
Line K. M. Lybech, Marco Calabro, Silvana Briuglia, Antonio Drago, Concetta Crisafulli
Summary: This study analyzed the genetic variants potentially associated with suicide behaviors in individuals with Bipolar Disorder (BD), indicating a relationship between suicide behaviors and alterations in entire pathways. Specific molecular events from the molecular pathway analysis may be the focus of further research in this field.
Article
Neurosciences
Yinan Wang, Ouxi Shen, Qingyun Xu, Lulu Sun, Yiming Jia, Yi Liu, Yu He, Xinyue Chang, Daoxia Guo, Mengyao Shi, Guo-Chong Chen, Jin Zheng, Zhengbao Zhu
Summary: This study used bidirectional 2-sample Mendelian randomization analyses and found that high orientation dispersion index in the right cerebral peduncle might be a potential causal mediator of amyotrophic lateral sclerosis. This finding may provide predictive guidance for the prevention of amyotrophic lateral sclerosis.
Article
Gastroenterology & Hepatology
M. D. Voskuil, L. M. Spekhorst, K. W. J. van der Sloot, B. H. Jansen, G. Dijkstra, C. J. van der Woude, F. Hoentjen, M. J. Pierik, A. E. van der Meulen, N. K. H. de Boer, M. Lowenberg, B. Oldenburg, E. A. M. Festen, R. K. Weersma
Summary: IBD phenotypes show significant heterogeneity between patients, and genetic risk scores [GRS] can help unravel the genetic contributions to these phenotypes. The study findings indicate that different CD and UC GRS are associated with specific IBD phenotypes, driven mainly by genetic variation.
JOURNAL OF CROHNS & COLITIS
(2021)
Article
Genetics & Heredity
Andrew R. Marderstein, Emily R. Davenport, Scott Kulm, Cristopher V. Van Hout, Olivier Elemento, Andrew G. Clark
Summary: The study demonstrates that prioritizing genetic variants associated with trait variance can improve GxE discovery rates and vQTLs are also enriched for associations with non-BMI phenotypes influenced by environmental factors. GxE effects identified in quantitative traits can also be utilized for GxE discovery in disease phenotypes.
AMERICAN JOURNAL OF HUMAN GENETICS
(2021)
Article
Immunology
Luzia Bruns, Victoria Panagiota, Sandra von Hardenberg, Gunnar Schmidt, Ignatius Ryan Adriawan, Eleni Sogka, Stefanie Hirsch, Gerrit Ahrenstorf, Torsten Witte, Reinhold Ernst Schmidt, Faranaz Atschekzei, Georgios Sogkas
Summary: This study investigated the prevalence of cancer and associated clinical, immunological, and genetic factors in a German cohort of patients with common variable immunodeficiency (CVID). The results showed that gastric cancer, non-melanoma skin cancer (NMSC), and non-Hodgkin lymphoma (NHL) were the most common types of cancer in CVID patients. Immune dysregulation manifested as arthritis, atrophic gastritis, or interstitial lung disease (ILD) was found to be associated with the diagnosis of cancer. The study concluded that studied immunological parameters or the identification of a monogenic form of CVID have a limited role in evaluating cancer risk in CVID.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Allergy
Xingnan Li, Huashi A. Li, Stephanie Christenson, Mario C. Castro, Loren C. Denlinger, Serpil V. Erzurum, John M. Fahy, Benjamin Gaston, Elliot N. Israel, Nizar D. Jarjour, Bruce Levy, David T. C. Mauger, Wendy Moore, Joe Zein, Naftali E. Kaminski, Sally G. Wenzel, Prescott R. Woodruff, Eugene A. Bleecker, Deborah Meyers
Summary: By combining SNPs and mRNA expression, we identified functional genes associated with asthma, including AP2A2 and MUC5AC. Higher expression of MUC5AC and lower expression of MUC5B were correlated with asthma severity. However, SNPs in the chr11p15.5 region were not associated with asthma severity or idiopathic interstitial pneumonias.
Article
Cardiac & Cardiovascular Systems
Mateusz Siedlinski, Lorenzo Carnevale, Xiaoguang Xu, Daniela Carnevale, Evangelos Evangelou, Mark J. Caulfield, Pasquale Maffia, Joanna Wardlaw, Nilesh J. Samani, Maciej Tomaszewski, Giuseppe Lembo, Michael Holmes, Tomasz J. Guzik
Summary: Observational and genetic data were used to study the relationship between blood pressure and cognitive function. The study identified brain structures associated with blood pressure and found that higher systolic blood pressure may have an adverse effect on cognitive function. These findings contribute to our understanding of the negative impact of hypertension on cognitive performance.
EUROPEAN HEART JOURNAL
(2023)
Review
Radiology, Nuclear Medicine & Medical Imaging
Santo Maimone, Laura K. Harper, Sarah K. Mantia, Pooja P. Advani, Alexander P. Hochwald, Zhuo Li, Stephanie L. Hines, Bhavika Patel
Summary: The purpose of this study was to examine the MRI phenotypes of breast cancers in patients with different pathogenic variants and assess imaging trends and associations. A retrospective review of 410 patients with breast cancer and a predisposing pathogenic variant who underwent breast MRI at time of cancer diagnosis was conducted. The study found that BRCA1 and BRCA2 variants were the most common, followed by CHEK2, ATM, and PALB2, with significant associations in race/ethnicity, age at cancer diagnosis, tumor characteristics, internal enhancement pattern, kinetics, and presence of necrosis. The conclusions suggest that genetic and molecular profiles of breast cancers demonstrate reproducible MRI phenotypes.
EUROPEAN JOURNAL OF RADIOLOGY
(2023)
Article
Ophthalmology
Inas F. Aboobakar, Tyler G. Kinzy, Yan Zhao, Baojian Fan, Louis R. Pasquale, Ayub Qassim, Antonia Kolovos, Joshua M. Schmidt, Jamie E. Craig, Jessica N. Cooke Bailey, Janey L. Wiggs, NEIGHBORHOOD Consortium
Summary: Genetic variants in the mitochondrial genes TXNRD2 and ME3 are associated with increased risk of POAG. This study constructed genetic risk scores for TXNRD2 and ME3 and found that higher GRSs are associated with higher intraocular pressure and higher prevalence of visual field loss in POAG patients. The study highlights the importance of investigating the impact of these variants on mitochondrial function in glaucoma patients.
Article
Biochemistry & Molecular Biology
Emanuele Monda, Michele Lioncino, Martina Caiazza, Vincenzo Simonelli, Claudia Nesti, Marta Rubino, Alessia Perna, Alfredo Mauriello, Alberta Budillon, Vincenzo Pota, Giorgia Bruno, Antonio Varone, Vincenzo Nigro, Filippo Maria Santorelli, Giuseppe Pacileo, Maria Giovanna Russo, Giulia Frisso, Simone Sampaolo, Giuseppe Limongelli
Summary: This study describes a group of patients with cardiomyopathy caused by neuromuscular diseases or mitochondrial diseases. The clinical phenotype of these patients was described through comprehensive clinical, molecular, and histological characteristics. A multidisciplinary evaluation and genetic testing play a key role in diagnosing these rare diseases.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Psychology, Clinical
Kaitlin E. Bountress, Daniel Bustamante, Stacey Subbie-Saenz De Viteri, Chris Chatzinakos, Christina Sheerin, Nikolaos P. Daskalakis, Howard J. Edenberg, Psychiatric Genomics Consortium Posttraumatic Stress Disorder Working Group, Roseann E. Peterson, Bradley T. Webb, Jackie Meyers, Ananda Amstadter
Summary: This study found that the genetic associations between consumption and problem alcohol phenotypes and PTSD differ in both strength and direction. The genetic factors that may lead someone to develop PTSD and high levels of alcohol consumption are not the same as those that lead someone to develop PTSD and alcohol-related problems.
PSYCHOLOGICAL MEDICINE
(2023)
Article
Clinical Neurology
Albert Z. Lim, Yi Shiau Ng, Alasdair Blain, Cecilia Jiminez-Moreno, Charlotte L. Alston, Victoria Nesbitt, Louise Simmons, Saikat Santra, Evangeline Wassmer, Emma L. Blakely, Doug M. Turnbull, Robert W. Taylor, Grainne S. Gorman, Robert McFarland
Summary: This study objectively defined the disease burden and progression of Leigh syndrome among children, revealing that functional decline and extrapyramidal features contribute significantly to disease burden. Predictors of poor outcomes include SURF1 gene variants and bilateral caudate changes on neuroimaging.
ANNALS OF NEUROLOGY
(2022)
Editorial Material
Genetics & Heredity
Valerio Carelli, Michio Hirano, Jose Antonio Enriquez, Patrick F. Chinnery
Summary: Individual cells in the same iPSC-derived clones exhibit large heterogeneity, with emerging evidence suggesting that variants in mitochondrial DNA play a pivotal role. Single-cell analyses have shown significant differences in the transcriptome between individual cells in the same iPSC-derived clones, which are partly attributable to genetic and epigenetic modifications of the nuclear genome.
NATURE REVIEWS GENETICS
(2022)
Article
Clinical Neurology
Yu Nie, Alexander Murley, Zoe Golder, James B. Rowe, Kieren Allinson, Patrick F. Chinnery
Summary: This study found that mtDNA variations are elevated in the temporal lobe of FTLD patients, particularly mtSNVs and mtDNA rearrangements. MtSNVs in the temporal lobe have a higher heteroplasmy rate and FTLD patients have a higher proportion of ribosomal gene variations affecting intra-mitochondrial protein synthesis and missense variations in genes coding for respiratory chain subunits.
ACTA NEUROPATHOLOGICA
(2022)
Correction
Genetics & Heredity
Anne Guimier, Melanie T. Achleitner, Anne Moreau de Bellaing, Matthew Edwards, Loic de Pontual, Kirti Mittal, Kyla E. Dunn, Megan E. Grove, Carolyn J. Tysoe, Clemantino Dimartino, Jessie Cameron, Anil Kanthi, Anju Shukla, Florence van den Broek, Diptendu Chatterjee, Charlotte L. Alston, Charlotte V. Knowles, Laura Brett, Jan A. Till, Tessa Homfray, Paul French, Georgia Spentzou, Noha A. Elserafy, Kate S. Lichkus, Bindu P. Sankaran, Hannah L. Kennedy, Peter M. George, Alexa Kidd, Saskia B. Wortmann, Dianna G. Fisk, Tamara T. Koopmann, Muhammad A. Rafiq, Jason D. Merker, Sumith Parikh, Priyanka Ahimaz, Robert G. Weintraub, Alan S. Ma, Christian Turner, Carolyn J. Ellaway, Liza K. Phillips, David R. Thorburn, Wendy K. Chung, Sajel L. Kana, Ona M. Faye-Petersen, Michelle L. Thompson, Alexandre Janin, Karen McLeod, Ruth McGowan, Robert McFarland, Katta M. Girisha, Deborah J. Morris-Rosendahl, Anna C. E. Hurst, Claire L. S. Turner, Robert M. Hamilton, Robert W. Taylor, Fanny Bajolle, Christopher T. Gordon, Jeanne Amiel, Johannes A. Mayr, Kit Doudney
GENETICS IN MEDICINE
(2022)
Article
Genetics & Heredity
Vicente A. Yepez, Mirjana Gusic, Robert Kopajtich, Christian Mertes, Nicholas H. Smith, Charlotte L. Alston, Rui Ban, Skadi Beblo, Riccardo Berutti, Holger Blessing, Elzbieta Ciara, Felix Distelmaier, Peter Freisinger, Johannes Haeberle, Susan J. Hayflick, Maja Hempel, Yulia S. Itkis, Yoshihito Kishita, Thomas Klopstock, Tatiana D. Krylova, Costanza Lamperti, Dominic Lenz, Christine Makowski, Signe Mosegaard, Michaela F. Mueller, Gerard Munoz-Pujol, Agnieszka Nadel, Akira Ohtake, Yasushi Okazaki, Elena Procopio, Thomas Schwarzmayr, Joel Smet, Christian Staufner, Sarah L. Stenton, Tim M. Strom, Caterina Terrile, Frederic Tort, Rudy Van Coster, Arnaud Vanlander, Matias Wagner, Manting Xu, Fang Fang, Daniele Ghezzi, Johannes A. Mayr, Dorota Piekutowska-Abramczuk, Antonia Ribes, Agnes Roetig, Robert W. Taylor, Saskia B. Wortmann, Kei Murayama, Thomas Meitinger, Julien Gagneur, Holger Prokisch
Summary: The lack of functional evidence hampers variant interpretation, but further sequencing of transcriptomes can help probe gene expression defects. A streamlined experimental and computational process involving RNA-seq analysis of skin fibroblasts led to the establishment of genetic diagnoses for 16% of WES-inconclusive cases, with detection of aberrant gene expression playing a major role in diagnosis, especially in identifying splice-disrupting variants.
Article
Genetics & Heredity
Claudia Calabrese, Angela Pyle, Helen Griffin, Jonathan Coxhead, Rafiqul Hussain, Peter S. Braund, Linxin Li, Annette Burgess, Patricia B. Munroe, Louis Little, Helen R. Warren, Claudia Cabrera, Alistair Hall, Mark J. Caulfield, Peter M. Rothwell, Nilesh J. Samani, Gavin Hudson, Patrick F. Chinnery
Summary: Heteroplasmic mitochondrial DNA mutations may play a role in the pathogenesis of cardiovascular diseases, particularly hypertension.
Article
Ophthalmology
Anna Majander, Neringa Jurkute, Florence Burte, Kristain Brock, Catarina Joao, Houbin Huang, Magella m. Neveu, Choi mun Chan, Holly j. Duncan, Simon Kelly, Emma Burkitt-Wright, Fadil Khoyratty, Yoon tse Lai, Mala Subash, Patrick f. Chinnery, Maria Bitner-Glindzicz, Gavin Arno, Andrew r. Webster, Anthony t. Moore, Michel Michaelides, Andrew Stockman, Anthony g. Robson, Patrick Yu-Wai-Man
Summary: This study evaluates the pattern of vision loss and genotype-phenotype correlations in WFS1-associated optic neuropathy (WON). The results show that WFS1 variants cause severe loss of retinal ganglion cells, but with some variability and correlation with the mode of inheritance.
AMERICAN JOURNAL OF OPHTHALMOLOGY
(2022)
Article
Genetics & Heredity
Joohyun Park, Arianna Tucci, Valentina Cipriani, German Demidov, Clarissa Rocca, Jan Senderek, Michaela Butryn, Ana Velic, Tanya Lam, Evangelia Galanaki, Elisa Cali, Letizia Vestito, Reza Maroofian, Natalie Deininger, Maren Rautenberg, Jakob Admard, Gesa-Astrid Hahn, Claudius Bartels, Nienke J. H. van Os, Rita Horvath, Patrick F. Chinnery, May Yung Tiet, Channa Hewamadduma, Marios Hadjivassiliou, George K. Tofaris, Nicholas W. Wood, Stefanie N. Hayer, Friedemann Bender, Benita Menden, Isabell Cordts, Katrin Klein, Huu Phuc Nguyen, Joachim K. Krauss, Christian Blahak, Tim M. Strom, Marc Sturm, Bart van de Warrenburg, Holger Lerche, Boris Macek, Matthis Synofzik, Stephan Ossowski, Dagmar Timmann, Marc E. Wolf, Damian Smedley, Olaf Riess, Ludger Schoels, Henry Houlden, Tobias B. Haack, Holger Hengel
Summary: This study investigated heterozygous variants in the UCHL1 gene and identified a novel disease mechanism associated with ataxia. Through gene-burden analyses and proteomics, it was found that haploinsufficiency of UCHL1 can cause neurodegenerative disorders.
GENETICS IN MEDICINE
(2022)
Article
Multidisciplinary Sciences
Wei Wei, Katherine R. Schon, Greg Elgar, Andrea Orioli, Melanie Tanguy, Adam Giess, Marc Tischkowitz, Mark J. Caulfield, Patrick F. Chinnery
Summary: The transfer of mitochondrial DNA into the nucleus contributes to a complex landscape of nuclear-mitochondrial segments (NUMTs). Almost all individuals have multiple NUMTs, including rare ones that are present in less than 0.1% of the population. Most NUMTs inserted into the nuclear genome after humans diverged from apes. Once inserted, the sequences are no longer under mitochondrial evolutionary constraints and have different mutational signatures compared to mitochondrial DNA.
Editorial Material
Clinical Neurology
Katherine R. Schon, Patrick F. Chinnery
PRACTICAL NEUROLOGY
(2023)
Article
Biochemistry & Molecular Biology
Camilla Ceccatelli Berti, Shalev Gihaz, Sonia Figuccia, Jae-Yeon Choi, Anasuya C. Pal, Paola Goffrini, Choukri Ben Mamoun
Summary: Human PANK1, PANK2, and PANK3 genes encode pantothenate kinase isoforms involved in Coenzyme A biosynthesis. Mutation in the PANK2 gene causes PKAN. This study demonstrates the functional conservation of PanK activity between humans and yeast, providing a model system for investigating the impact of PKAN-associated mutations.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Biochemistry & Molecular Biology
Martina Magistrati, Alexandru Ionut Gilea, Camilla Ceccatelli Berti, Enrico Baruffini, Cristina Dallabona
Summary: In eukaryotes, specific nucleotide modifications of mitochondrial RNAs play critical roles in the synthesis of mitochondrial proteins and oxidative phosphorylation. Mutations in genes encoding for mt-RNAs modifying enzymes can cause modopathies. These mutations lead to the absence or decrease of specific nucleotide modifications, impairing the efficiency and accuracy of mitochondrial protein synthesis. Confirmation of their pathogenicity through a model system, such as Saccharomyces cerevisiae, is essential.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Genetics & Heredity
Laura S. Kremer, Lyuba V. Bozhilova, Diana Rubalcava-Gracia, Roberta Filograna, Mamta Upadhyay, Camilla Koolmeister, Patrick F. Chinnery, Nils-Goran Larsson
Summary: In this study, the role of autophagy in germline purifying selection of mtDNA was investigated by mating different autophagy-deficient mouse models with mice carrying a pathogenic tRNA(Ala) gene mutation. The results showed that Bcl2l13 had a significant effect on the selection process, while Ulk1 and Ulk2 had weaker effects, and Parkin had no statistically significant impact. This study provides experimental evidence for the distinct roles of autophagy in germline purifying selection of mtDNA and establishes a framework for future studies on this process.
Article
Genetics & Heredity
Alexander G. Murley, Yu Nie, Zoe Golder, Michael John Keogh, Colin Smith, James W. Ironside, Patrick F. Chinnery
Summary: This study investigated the role of pathologic somatic variants in the PRNP gene in sporadic Creutzfeldt-Jakob disease (sCJD). High-depth amplicon-based sequencing was performed on postmortem brain tissue from sCJD, Alzheimer's disease, and control subjects. The study found somatic PRNP variants in sCJD cases, but their pathogenicity remains uncertain.
NEUROLOGY-GENETICS
(2023)
Article
Clinical Neurology
Saeed Kayhanian, Angelos Glynos, Richard Mair, Andras Lakatos, Peter J. A. Hutchinson, Adel E. Helmy, Patrick F. Chinnery
Summary: Traumatic brain injury and aneurysmal subarachnoid haemorrhage are significant global diseases with limited treatment options. This research found elevated levels of cell-free mtDNA in both cerebrospinal fluid and serum within 48 hours of brain injury, which correlated with clinical severity and inflammatory response. These findings suggest that ccf-mtDNA could serve as a biomarker for inflammation-related acute brain injury.
NEUROTRAUMA REPORTS
(2022)