Review
Ophthalmology
Michael P. Fautsch, Eric D. Wieben, Keith H. Baratz, Nihar Bhattacharyya, Amanda N. Sadan, Nathaniel J. Hafford-Tear, Stephen J. Tuft, Alice E. Davidson
Summary: FECD is a common cause of heritable visual loss in the elderly, with an association to an intronic CTG trinucleotide repeat expansion in the TCF4 gene. Proposed mechanisms for disease onset include TCF4 dysregulation, toxic gain-of-function from TCF4 repeat-containing RNA, toxic gain-of-function from RAN translation, and somatic instability of CTG18.1, but the relative contribution of each remains unknown.
PROGRESS IN RETINAL AND EYE RESEARCH
(2021)
Article
Ophthalmology
Jiaxin Hu, Xin Gong, Samantha T. Johnson, David R. Corey, V. Vinod Mootha
Summary: In the United States, the majority of Fuchs' endothelial corneal dystrophy (FECD) cases are caused by an intronic trinucleotide repeat expansion in the TCF4 gene. This study aimed to detect the presence of RNA foci in different anterior segment cell types and assess their molecular impact. The results showed that CUG repeat RNA foci are most prevalent in corneal endothelial cells and less detectable in other cell types.
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
(2023)
Article
Ophthalmology
Bhumi B. Kinariwala, Timothy T. Xu, Keith H. Baratz, Ross A. Aleff, Sanjay Patel, Leo J. Maguire, Michael P. Fautsch, Eric D. Wieben, Amy E. Millen, Sangita P. Patel
Summary: This study found a positive association between body mass index (BMI) and Fuchs endothelial corneal dystrophy (FECD) severity in women, but not in men. Additionally, there was no significant association between BMI and CTG18.1 expansion. These results suggest that increased BMI may be a modifiable risk factor for FECD disease progression among women.
Article
Multidisciplinary Sciences
Eric D. Wieben, Ross A. Aleff, Tommy A. Rinkoski, Keith H. Baratz, Shubham Basu, Sanjay Patel, Leo J. Maguire, Michael P. Fautsch
Summary: Analysis of CTG TNR expansion in FECD patients revealed significantly longer repeat lengths in the corneal endothelium compared to leukocytes.
Article
Ophthalmology
Andreas Viberg, Ida Maria Westin, Irina Golovleva, Berit Bystrom
Summary: In northern Sweden, almost 90% of FECD patients have a (CTG)(n) repeat expansion in the TCF4 gene, with repeat length being associated with disease severity. Additionally, FECD cases without a TCF4 repeat expansion have a higher rate of ocular surgery compared to those with a repeat expansion.
ACTA OPHTHALMOLOGICA
(2022)
Article
Cell Biology
Chase P. Kelley, Maja C. Haerle, Eric T. Wang
Summary: CRISPR-Cas13 RNA endonucleases have the potential for programmable RNA knockdown, but concerns have been raised about their collateral activity. This study investigates the collateral activity of Cas13d in the therapeutic context of myotonic dystrophy type 1 and finds that it interferes with cellular processes and activates stress response and apoptosis. The introduction of the GENO strategy is proposed to minimize collateral activity for repeat-targeting approaches.
Article
Ophthalmology
Gozde Sahin Vural, Hilmi Bolat
Summary: This study evaluated the relationship between the number of trinucleotide repeats (TNR) in late-onset Fuchs corneal endothelial dystrophy (FCED) and compared the endothelial properties among FCED patients, first-degree relatives, and controls. The study found that FCED patients and relatives had lower corneal thickness and endothelial cell density compared to controls, and significant endothelial cell morphological changes were observed. Additionally, the number of TNR in FCED patients was correlated with the corneal endothelial properties in relatives.
GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY
(2023)
Article
Multidisciplinary Sciences
M. E. Cicardi, J. H. Hallgren, D. Mawrie, K. Krishnamurthy, S. S. Markandaiah, A. T. Nelson, V. Kankate, E. N. Anderson, P. Pasinelli, U. B. Pandey, C. M. Eischen, D. Trotti
Summary: The intronic hexanucleotide repeat expansion in the C9orf72 gene is translated into dipeptide repeat proteins, specifically poly proline-arginine (PR), which accumulates in the nucleolus and causes nucleolar stress and increased p53 levels in neurons. Decreasing p53 levels can reduce PR-induced neurotoxicity, and PR does not induce senescence but rather programmed cell death via caspase-3 activation.
Article
Chemistry, Multidisciplinary
Jiaxin Hu, Xiulong Shen, Mahboubeh Kheirabadi, Matthew D. Streeter, Ziqing Qian, V. Vinod Mootha, David R. Corey
Summary: Fuchs' corneal endothelial dystrophy (FECD) is a major cause of vision loss and currently, corneal transplantation is the only effective treatment option. However, there are limitations to this surgery and a pharmacological intervention could benefit many patients. In this study, the researchers evaluated the use of anti-CUG morpholinos conjugated to cyclic cell penetrating peptides and demonstrated their ability to enter corneal endothelial cells and block the CUG RNA foci associated with FECD.
Article
Genetics & Heredity
Ida Maria Westin, Andreas Viberg, Berit Bystrom, Irina Golovleva
Summary: FECD is associated with the CTG18.1 trinucleotide repeat expansion in the TCF4 gene, affecting expression of different TCF4 transcripts subtly. The fraction of transcripts spanning over CTG18.1 tract is lower in corneal endothelium compared to other tissues studied.
Article
Ophthalmology
Shazia Ashraf, Neha Deshpande, Shivakumar Vasanth, Geetha Melangath, Raymond J. Wong, Yan Zhao, Marianne O. Price, Francis W. Price Jr, Ula V. Jurkunas
Summary: Fuchs Endothelial Corneal Dystrophy (FECD) is a common cause of corneal endothelial degeneration and is associated with CTG repeat expansion in TCF4 gene. Accumulation of nuclear and mitochondrial DNA damage was observed in FECD, with mtDNA damage being prominent in the UVA-induced FECD mouse model. Impaired DNA repair pathways were identified in FECD specimens through analysis of gene expression profiles. These findings suggest that DNA repair dysfunction may contribute to the increased DNA damage seen in FECD.
EXPERIMENTAL EYE RESEARCH
(2023)
Article
Multidisciplinary Sciences
Makito Hirano, Motoi Kuwahara, Yuko Yamagishi, Makoto Samukawa, Kanako Fujii, Shoko Yamashita, Masahiro Ando, Nobuyuki Oka, Mamoru Nagano, Taro Matsui, Toshihide Takeuchi, Kazumasa Saigoh, Susumu Kusunoki, Hiroshi Takashima, Yoshitaka Nagai
Summary: This study found RFC1 mutations related to CANVAS in patients with treatable immune-mediated neuropathy or demyelinating neuropathy.
SCIENTIFIC REPORTS
(2023)
Review
Medicine, General & Internal
Eleonora S. D'Ambrosio, Paloma Gonzalez-Perez
Summary: Myotonic dystrophy (DM) is the most common muscular dystrophy in adults, caused by repeat expansions in DMPK and CNBP genes. DM patients have a higher risk of cancer, but there are no specific screening guidelines for malignancy. This review highlights the importance of monitoring malignancy screenings in DM patients and the need for further studies on intensified cancer screening for this population.
JOURNAL OF CLINICAL MEDICINE
(2023)
Article
Biochemical Research Methods
Shinichi Morishita, Kazuki Ichikawa, Eugene W. Myers
Summary: This study presents an efficient algorithm that utilizes the characteristics of repetitive sequences to address the issue of high error rates in long-read sequencing technologies. The algorithm first estimates regions that may contain tandem repeats, and then assembles the k-mers of these regions into a consensus repeat unit by greedily traversing a de Bruijn graph. Experimental results demonstrate that the proposed algorithm outperforms the widely used Tandem Repeats Finder in terms of sensitivity.
Article
Genetics & Heredity
Lubica Dudakova, Pavlina Skalicka, Alice E. Davidson, Amanda N. Sadan, Monika Chylova, Helena Jahnova, Nicole Anteneova, Marketa Tesarova, Tomas Honzik, Petra Liskova
Summary: This study aimed to describe the ocular phenotype in a case with Kearns-Sayre syndrome (KSS) spectrum and investigate the potential genetic causes of corneal endothelial cell dysfunction. Exome sequencing and genotyping revealed no pathogenic variants in genes associated with corneal endothelial dystrophies, while a repeat expansion in TCF4 gene and mtDNA deletion were found in the patient with KSS spectrum. Rare ocular findings included marked corneal oedema, emphasizing the complex manifestations of ocular abnormalities in KSS spectrum.
Article
Ophthalmology
Matthew T. Fenech, Giulia Coco, Luca Pagano, Kunal A. Gadhvi, Mitchell Titley, Hannah J. Levis, Mohit Parekh, Stephen B. Kaye, Vito Romano
Summary: This study aimed to describe the changes in corneal graft thickness following ultrathin Descemet's Stripping Automated Endothelial Keratoplasty (UT-DSAEK) over a 24-month period. The results showed that the preoperative measurements of graft thickness can serve as a reliable approximation of the thickness at 6 months after surgery, and these measurements tend to stabilize over time up to 2 years after surgery. The graft thickness gradually decreased after surgery and plateaued at 12 months.
Review
Ophthalmology
Mohit Parekh, Davide Romano, Rintra Wongvisavavit, Giulia Coco, Giuseppe Giannaccare, Stefano Ferrari, Carlos Rocha-de-Lossada, Hannah J. Levis, Francesco Semeraro, Marina Rodriguez Calvo-de-Mora, Vincenzo Scorcia, Vito Romano
Summary: Descemet membrane endothelial keratoplasty (DMEK) is a popular surgical procedure for treating Fuchs endothelial corneal dystrophy (FECD) and pseudophakic bullous keratopathy (PBK). The size of the graft is crucial for the success of the procedure, with smaller grafts being preferred. However, larger diameter grafts pose challenges due to higher detachment rates.
ACTA OPHTHALMOLOGICA
(2023)
Article
Genetics & Heredity
Linda M. Reis, Mohit Maheshwari, Jenina Capasso, Huban Atilla, Lubica Dudakova, Samuel Thompson, Lia Zitano, Guillermo Lay-Son, R. Brian Lowry, Jennifer Black, Joseph Lee, Ann Shue, Radka Kremlikova Pourova, Manuela Vaneckova, Pavlina Skalicka, Jana Jedlickova, Marie Trkova, Bradley Williams, Gabriele Richard, Kristine Bachman, Andrea H. Seeley, Deborah Costakos, Thomas M. Glaser, Alex Levin, Petra Liskova, Jeffrey C. Murray, Elena Semina
Summary: This study investigated the genetic and phenotypic characteristics of the largest reported cohort of individuals with Axenfeld-Rieger syndrome (ARS). The findings revealed that there are distinct phenotypic differences between ARS subtypes caused by mutations in PITX2 and FOXC1 genes, including variations in ocular and systemic anomalies, age of onset of glaucoma, and associated features such as dental abnormalities and structural anomalies in the digestive system. The expanded phenotype of FOXC1-related ARS was also found to overlap with De Hauwere syndrome. These findings highlight the importance of providing families with a gene-specific diagnosis and management plan for ARS.
JOURNAL OF MEDICAL GENETICS
(2023)
Article
Ophthalmology
Giulia Coco, Hannah J. Levis, Alfredo Borgia, Davide Romano, Luca Pagano, Gianni Virgili, Stephen B. Kaye, Vito Romano
Summary: By evaluating the features of anterior segment optical coherence tomography (AS-OCT), it was found that posterior stromal ripples and detachment axial extension are the main risk factors for graft detachment worsening in Descemet's membrane endothelial keratoplasty (DMEK). Patients showing these features should be closely monitored to identify the need for re-bubbling at an early stage, thus improving surgical outcomes.
ACTA OPHTHALMOLOGICA
(2023)
Article
Biochemistry & Molecular Biology
Yan Chen, Pirro Hysi, Carlo Maj, Stefanie Heilmann-Heimbach, Timothy D. Spector, Fan Liu, Manfred Kayser
Summary: The newly presented genetic prediction models for male pattern baldness (MPB) based on a large set of markers and large independent subsample sets are considered the most reliable ones currently available for MPB or any other human appearance trait.
EUROPEAN JOURNAL OF HUMAN GENETICS
(2023)
Article
Ophthalmology
Siyin Liu, Amanda N. Sadan, Kirithika Muthusamy, Christina Zarouchlioti, Jana Jedlickova, Nikolas Pontikos, Caroline Thaung, Alison J. Hardcastle, Magdalena Netukova, Pavlina Skalicka, Lubica Dudakova, Catey Bunce, Stephen J. Tuft, Alice E. Davidson, Petra Liskova
Summary: This study characterized the phenotype and genotype of patients with concurrent keratoconus and Fuchs endothelial corneal dystrophy (KC + FECD). The results showed that the phenotype of KC + FECD is similar to keratoconus but with added stromal swelling from endothelial disease. Among these patients, 35% had a TCF4 expansion, which was similar in proportion to age-matched controls with isolated FECD.
ACTA OPHTHALMOLOGICA
(2023)
Article
Genetics & Heredity
Jana Jedlickova, Marie Vajter, Tomas Barta, Graeme C. M. Black, Rahat Perveen, Jan Mares, Marek Fichtl, Bohdan Kousal, Lubica Dudakova, Petra Liskova
Summary: Four members of a three-generation Czech family were found to carry the n.37C>T variant in MIR204, leading to early-onset chorioretinal dystrophy. This study confirmed the existence of a distinct clinical entity caused by this genetic mutation. Chorioretinal dystrophy was found to be associated with iris coloboma, congenital glaucoma, and premature cataracts, expanding the phenotypic range. In silico analysis of the variant revealed 713 new targets. Additionally, albinism caused by biallelic pathogenic OCA2 variants was observed in four family members. Haplotype analysis ruled out relatedness with the original family reported to have the n.37C>T variant in MIR204. The identification of a second independent family further confirms the existence of a distinct MIR204-associated clinical entity and suggests a potential involvement of congenital glaucoma in the phenotype.
Article
Multidisciplinary Sciences
Oana A. Zeleznik, Jae H. Kang, Jessica Lasky-Su, A. Heather Eliassen, Lisa Frueh, Clary B. Clish, Bernard A. Rosner, Tobias Elze, Pirro Hysi, Anthony Khawaja, Janey L. Wiggs, Louis R. Pasquale
Summary: Glaucoma is a leading cause of irreversible blindness worldwide, but its etiology is poorly understood. This study aimed to identify plasma metabolites associated with the risk of primary open-angle glaucoma (POAG) using case-control studies and cross-sectional studies. The results showed that higher levels of diglycerides and triglycerides were adversely associated with glaucoma, indicating their important role in glaucoma pathogenesis.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Joseph Towler, Alejandra Consejo, Dong Zhou, Vito Romano, Hannah Levis, Craig Boote, Ahmed Elsheikh, Brendan Geraghty, Ahmed Abass
Summary: This study presents an averaged anterior eye geometry model combined with a localised material model that is suitable for finite element modelling. The averaged geometry model was constructed using eye profile data from 118 subjects, while the localised material model was built using collagen microstructure x-ray data from healthy human eyes. The study found that the stresses generated in the inflation simulation differed significantly between the ring-segmented material model and the localised element-specific material model.
Article
Genetics & Heredity
Janine Reurink, Nicole Weisschuh, Alejandro Garanto, Adrian Dockery, L. Ingeborgh van den Born, Isabelle Fajardy, Lonneke Haer-Wigman, Susanne Kohl, Bernd Wissinger, G. Jane Farrar, Tamar Ben-Yosef, Fatma Kivrak Pfiffner, Wolfgang Berger, Marianna E. Weener, Lubica Dudakova, Petra Liskova, Dror Sharon, Manar Salameh, Ashley Offenheim, Elise Heon, Giorgia Girotto, Paolo Gasparini, Anna Morgan, Arthur A. Bergen, Jacoline B. ten Brink, Caroline C. W. Klaver, Lisbeth Tranebjaerg, Nanna D. Rendtorff, Sascha Vermeer, Jeroen J. Smits, Ronald J. E. Pennings, Marco Aben, Jaap Oostrik, Galuh D. N. Astuti, Jordi Corominas Galbany, Hester Y. Kroes, Milan Phan, Wendy A. G. van Zelst-Stams, Alberta A. H. J. Thiadens, Joke B. G. M. Verheij, Mary J. van Schooneveld, Suzanne E. de Bruijn, Catherina H. Z. Li, Carel B. Hoyng, Christian Gilissen, Lisenka E. L. M. Vissers, Frans P. M. Cremers, Hannie Kremer, Erwin van Wijk, Susanne Roosing
Summary: Whole genome sequencing combined with an improved variant interpretation pipeline was used to assess individuals suspected of having USH2A-associated disease, leading to the identification of causative variants and providing a conclusive genetic diagnosis for rare genetic conditions.
HUMAN GENETICS AND GENOMICS ADVANCES
(2023)
Letter
Dermatology
Fuduan Peng, Ziyi Xiong, Gu Zhu, Pirro G. Hysi, Ryan J. Eller, Sijie Wu, Kaustubh Adhikari, Yan Chen, Yi Li, Rolando Gonzalez-Jose, Lavinia Schuler-Faccini, Maria-Catira Bortolini, Victor Acuna-Alonzo, Samuel Canizales-Quinteros, Carla Gallo, Giovanni Poletti, Gabriel Bedoya, Francisco Rothhammer, Andre G. Uitterlinden, M. Arfan Ikram, Tamar Nijsten, Andres Ruiz-Linares, Sijia Wang, Susan Walsh, Timothy D. Spector, Nicholas G. Martin, Manfred Kayser, Fan Liu
JOURNAL OF INVESTIGATIVE DERMATOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Ashley van der Spek, Isobel D. Stewart, Brigitte Kuehnel, Maik Pietzner, Tahani Alshehri, Friederike Gauss, Pirro G. Hysi, Siamak MahmoudianDehkordi, Almut Heinken, Annemarie I. Luik, Karl-Heinz Ladwig, Gabi Kastenmueller, Cristina Menni, Johannes Hertel, M. Arfan Ikram, Renee de Mutsert, Karsten Suhre, Christian Gieger, Konstantin Strauch, Henry Voelzke, Thomas Meitinger, Massimo Mangino, Antonia Flaquer, Melanie Waldenberger, Annette Peters, Ines Thiele, Rima Kaddurah-Daouk, Boadie W. Dunlop, Frits R. Rosendaal, Nicholas J. Wareham, Tim D. Spector, Sonja Kunze, Hans Joergen Grabe, Dennis O. Mook-Kanamori, Claudia Langenberg, Cornelia M. van Duijn, Najaf Amin
Summary: The study identified 8 metabolites associated with depression through metabolome-wide association analysis. These metabolites are either directly derived from food or products of host and gut microbial metabolism of food-derived products. The findings highlight the potential of diet interventions in preventing depression.
MOLECULAR PSYCHIATRY
(2023)
Article
Multidisciplinary Sciences
Wendy W. Liu, Tyler G. Kinzy, Jessica N. Cooke Bailey, Zihe Xu, Pirro Hysi, Janey L. Wiggs, NEIGHBORHOOD Consortium
Summary: This study investigated the associations between gene variants of mechanosensitive ion channels and primary open-angle glaucoma (POAG), a disease modulated by eye pressure. The researchers identified several rare and common variants in these ion channel genes that showed associations with POAG, suggesting these channels may be potential therapeutic targets.
SCIENTIFIC REPORTS
(2023)
