Article
Medicine, General & Internal
Guoliang Chai, Emmanuelle Szenker-Ravi, Changuk Chung, Zhen Li, Lu Wang, Muznah Khatoo, Trevor Marshall, Nan Jiang, Xiaoxu Yang, Jennifer McEvoy-Venneri, Valentina Stanley, Paula Anzenberg, Nhi Lang, Vanessa Wazny, Jia Yu, David M. Virshup, Rie Nygaard, Filippo Mancia, Rijad Merdzanic, Maria B. P. Toralles, Paula M. L. Pitanga, Ratna D. Puri, Rebecca Hernan, Wendy K. Chung, Aida M. Bertoli-Avella, Nouriya Al-Sannaa, Maha S. Zaki, Karl Willert, Bruno Reversade, Joseph G. Gleeson
Summary: This study identified homozygous mutations in WLS in patients with syndromic structural birth defects, affecting Wnt protein secretion and signaling. Mouse models showed potential for pharmacologic intervention to prevent Zaki syndrome.
NEW ENGLAND JOURNAL OF MEDICINE
(2021)
Article
Genetics & Heredity
Seungbok Lee, Soojin Park, Hwa Young Kim, Jong Hee Chae, Jung Min Ko
Summary: The study presents a rare case of a patient with lymphatic dysplasia caused by compound heterozygous variants of PIEZO1, along with skeletal phenotypes as additional clinical manifestations.
EUROPEAN JOURNAL OF MEDICAL GENETICS
(2021)
Article
Biochemistry & Molecular Biology
Shang Ma, Adrienne E. Dubin, Yunxiao Zhang, Seyed Ali Reza Mousavi, Yu Wang, Adam M. Coombs, Meaghan Loud, Immacolata Andolfo, Ardem Patapoutian
Summary: Iron overload can cause progressive organ damage and is associated with genetic factors affecting iron homeostasis. Certain individuals with hereditary disorders may develop iron overload, and some GOF PIEZO1 alleles are linked to iron imbalance. The study demonstrates the key role of PIEZO1 in macrophage phagocytic activity and iron metabolism, with a particular GOF PIEZO1 allele showing a strong association with increased plasma iron levels in individuals of African descent.
Article
Immunology
Frederik Staels, Kerstin De Keukeleere, Matias Kinnunen, Salla Keskitalo, Flaminia Lorenzetti, Michiel Vanmeert, Teresa Prezzemolo, Emanuela Pasciuto, Eveline Lescrinier, Xavier Bossuyt, Margaux Gerbaux, Mathijs Willemsen, Julika Neumann, Sien Van Loo, Anniek Corveleyn, Karen Willekens, Ingeborg Stalmans, Isabelle Meyts, Adrian Liston, Stephanie Humblet-Baron, Mikko Seppanen, Markku Varjosalo, Rik Schrijvers
Summary: NFKB1 haploinsufficiency is a common variable immunodeficiency characterized by increased susceptibility to infections, skin lesions, malignant lymphoproliferation, and autoimmunity. Over 50 mutations have been reported, with the majority located in the N-terminal Rel homology domain. Two novel variants in NFKB1 were found in two families with CVID, proving their pathogenicity.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Multidisciplinary Sciences
Julia Kornienko, Marta Rodriguez-Martinez, Kai Fenzl, Florian Hinze, Daniel Schraivogel, Markus Grosch, Brigit Tunaj, Dominik Lindenhofer, Laura Schraft, Moritz Kueblbeck, Eric Smith, Chad Mao, Emily Brown, Anjali Owens, Ardan M. M. Saguner, Benjamin Meder, Victoria Parikh, Michael Gotthardt, Lars M. M. Steinmetz
Summary: The authors demonstrate that loss of interaction with the nuclear importer TNPO3 leads to cytoplasmic mislocalization of RBM20 variants associated with severe dilated cardiomyopathy. Restoring their nuclear localization can alleviate the disease phenotype. These findings provide insight into the molecular mechanism of RBM20 mislocalization and its role in dilated cardiomyopathy.
NATURE COMMUNICATIONS
(2023)
Review
Clinical Neurology
Kathryn J. Peall, Michael J. Owen, Jeremy Hall
Summary: Understanding rare genetic brain disorders with overlapping neurological and psychiatric phenotypes is important for studying more common polygenic disorders. However, the clinical boundaries between neurology and psychiatry often limit cross-specialty understanding and advances in research.
NATURE REVIEWS NEUROLOGY
(2023)
Article
Immunology
Yingyue Zhou, Mari Tada, Zhangying Cai, Prabhakar S. Andhey, Amanda Swain, Kelly R. Miller, Susan Gilfillan, Maxim N. Artyomov, Masaki Takao, Akiyoshi Kakita, Marco Colonna
Summary: Colonna and colleagues found dysregulated gene expression in microglia with DAP12 mutations in individuals with Nasu-Hakola disease. The TREM2-DAP12 receptor complex is important for microglial function. Heterozygous hypofunctional TREM2 variants can lead to late-onset Alzheimer's disease.
Article
Biochemistry & Molecular Biology
Linda M. Reis, Nicolas Chassaing, Tanya Bardakjian, Samuel Thompson, Adele Schneider, Elena V. Semina
Summary: ARHGAP35 plays roles in cell migration, invasion and division, neuronal morphogenesis, and gene/mRNA regulation. Studies have shown its involvement in cancer and developmental disorders. This study identified damaging variants in ARHGAP35 in individuals with eye and non-eye-related phenotypes, suggesting its importance in human developmental eye phenotypes. Further studies are needed to understand the underlying mechanism.
EUROPEAN JOURNAL OF HUMAN GENETICS
(2023)
Article
Biophysics
Dario De Vecchis, David J. Beech, Antreas C. Kalli
Summary: Through molecular dynamics simulations, it was found that membrane stretching causes Piezo1 to flatten and expand its blade region, resulting in tilting and lateral movement of the pore-lining transmembrane helices 37 and 38. This leads to the opening of the channel and the movement of lipids out of the pore region.
BIOPHYSICAL JOURNAL
(2021)
Article
Biochemistry & Molecular Biology
Dantong Li, Miaoyue Hu, Huamu Chen, Xiaohong Wu, Xiaoya Wei, Hongrong Lin, Xuefei Gao, Haiyan Wang, Min Li, Albert C. M. Ong, Zhihui Yue, Liangzhong Sun
Summary: This study successfully created a knockout mouse model of the Nphp1 gene, which faithfully recapitulated the renal and extrarenal phenotypes associated with human NPH. This model will be valuable for studying Nphp1 function and developing novel treatments for this common childhood disease.
HUMAN MOLECULAR GENETICS
(2022)
Article
Ophthalmology
S. U. S. H. M. I. T. A. Kaushik, S. A. N. D. E. E. P. Choudhary, A. N. U. P. R. I. Y. A. Kaur, P. R. I. Y. A. N. K. A. Srivastava, B. I. K. R. A. N. T. Pokharel, M. A. D. H. U. R. Akella, Surinder Singh Pandav
Summary: This study reports the underlying genetic variants of a newly described distinct phenotype of newborn glaucoma called neonatal-onset congenital ectropion uveae (NO-CEU). Through clinical exome sequencing of 13 children with NO-CEU, the study identified CYP1B1 variants associated with the phenotype. The findings also showed that different genotypes have an impact on ocular manifestations and visual outcomes in these patients.
AMERICAN JOURNAL OF OPHTHALMOLOGY
(2022)
Review
Cell Biology
Akira Sugiyama, Masanori Hirashima
Summary: Fetal nuchal edema is associated with various fetal malformations, but the causative genes and prognosis have not been fully understood in humans. However, using mouse models, it has been shown that many gene mutations can cause fetal nuchal edema and other anomalies, which is important for developing diagnostic methods and predicting prognosis.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Dermatology
L. Harjama, V. Karvonen, K. Kettunen, O. Elomaa, E. Einarsdottir, H. Heikkila, S. Kivirikko, P. Ellonen, J. Saarela, A. Ranki, J. Kere, K. Hannula-Jouppi
Summary: Hereditary palmoplantar keratodermas (PPK) is a group of rare skin disorders characterized by epidermal hyperkeratosis of the palms and soles, with mutations in at least 69 genes implicated. In a cohort of 64 patients, pathogenic mutations were identified in five genes: AQP5, AAGAB, KRT9, SERPINB7, and SLURP1, with diffuse PPK being the most common presentation.
JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY
(2021)
Article
Genetics & Heredity
Ellen F. Gregory, Shilpi Kalra, Trisha Brock, Gisele Bonne, G. W. Gant Luxton, Christopher Hopkins, Daniel A. Starr
Summary: This study created Caenorhabditis elegans models to study striated muscle laminopathies caused by LMNA gene mutations. Severe missense variants reduced fertility and motility in worms, and nuclear morphology defects were observed. The study provided insights into lamin mechanisms during normal development of laminopathies.
Article
Dentistry, Oral Surgery & Medicine
J. Chen, X. Yuan, I. Pilawski, X. Liu, J. Delgado-Calle, T. Bellido, H. Turkkahraman, J. A. Helms
Summary: Genetic disorders can result in distinctive facial features, affecting diagnosis and treatment. Using a mouse model, this study found that mutations in the Sost gene led to abnormal bone growth, causing changes in facial skeletal morphology and size, suggesting a role for sclerostin signaling in modulating craniofacial morphology.
JOURNAL OF DENTAL RESEARCH
(2021)
Review
Cardiac & Cardiovascular Systems
Richard M. Monaghan, Donna J. Page, Pia Ostergaard, Bernard D. Keavney
Summary: VEGFR3 plays crucial roles in the development of lymphovascular and cardiovascular systems, with genetic variations in FLT4 leading to distinct human conditions like hereditary primary lymphoedema and Tetralogy of Fallot, highlighting the multifaceted nature of this receptor.
CARDIOVASCULAR RESEARCH
(2021)
Article
Medicine, Research & Experimental
Kristiana Gordon, Peter S. Mortimer, Malou van Zanten, Steve Jeffery, Pia Ostergaard, Sahar Mansour
Summary: Clinicians and scientists at St George's University Hospital have collaborated to develop a classification algorithm for primary lymphatic anomalies, providing guidance for clinical practice. The algorithm not only refines the diagnosis, but also guides genetic testing and management, as well as interpretation of mutation testing results of uncertain significance.
LYMPHATIC RESEARCH AND BIOLOGY
(2021)
Review
Radiology, Nuclear Medicine & Medical Imaging
Michael Mills, Malou van Zanten, Marco Borri, Peter S. Mortimer, Kristiana Gordon, Pia Ostergaard, Franklyn A. Howe
Summary: Magnetic resonance lymphangiography (MRL) is a noninvasive technique that can assess lymphatic drainage, providing 3D imaging of the lymphatic vasculature. Further research is needed to optimize protocol design and fully realize the potential of MRL in improving understanding and detection of lymphatic diseases.
JOURNAL OF MAGNETIC RESONANCE IMAGING
(2021)
Review
Physiology
Silvia Martin-Almedina, Peter S. Mortimer, Pia Ostergaard
Summary: Primary lymphedema is a chronic condition characterized by tissue lymph retention and swelling, often affecting any part of the body. Dysfunction in the lymphatic system can have wide-ranging effects on immune function, cancer development, and fat transport. Genetic studies have shown primary lymphedema to be heterogenous in genetic causes and disease mechanisms.
PHYSIOLOGICAL REVIEWS
(2021)
Article
Genetics & Heredity
Silvia Martin-Almedina, Kazim Ogmen, Ege Sackey, Dionysios Grigoriadis, Christina Karapouliou, Noeline Nadarajah, Cathrine Ebbing, Jenny Lord, Rhiannon Mellis, Fanny Kortuem, Mary Beth Dinulos, Cassandra Polun, Sherri Bale, Giles Atton, Alexandra Robinson, Hallvard Reigstad, Gunnar Houge, Axel von der Wense, Wolf-Henning Becker, Steve Jeffery, Peter S. Mortimer, Kristiana Gordon, Katherine S. Josephs, Sarah Robart, Mark D. Kilby, Stephanie Vallee, Jerome L. Gorski, Maja Hempel, Siren Berland, Sahar Mansour, Pia Ostergaard
Summary: This study reveals that novel variants of EPHB4 have different pathogenic mechanisms in various clinical phenotypes, and protein expression and subcellular localization studies are helpful in predicting the pathogenesis of EPHB4 variants. The study also uncovers the occurrence of intrafamilial overlapping phenotypes such as lymphatic-related fetal hydrops and CM-AVM2.
GENETICS IN MEDICINE
(2021)
Correction
Genetics & Heredity
Silvia Martin-Almedina, Kazim Ogmen, Ege Sackey, Dionysios Grigoriadis, Christina Karapouliou, Noeline Nadarajah, Cathrine Ebbing, Jenny Lord, Rhiannon Mellis, Fanny Kortuem, Mary Beth Dinulos, Cassandra Polun, Sherri Bale, Giles Atton, Alexandra Robinson, Hallvard Reigstad, Gunnar Houge, Axel von der Wense, Wolf-Henning Becker, Steve Jeffery, Peter S. Mortimer, Kristiana Gordon, Katherine S. Josephs, Sarah Robart, Mark D. Kilby, Stephanie Vallee, Jerome L. Gorski, Maja Hempel, Siren Berland, Sahar Mansour, Pia Ostergaard
GENETICS IN MEDICINE
(2021)
Article
Medicine, Research & Experimental
Oliver Lyons, James Walker, Christopher Seet, Mohammed Ikram, Adam Kuchta, Andrew Arnold, Magda Hernandez-Vasquez, Maike Frye, Gema Vizcay-Barrena, Roland A. Fleck, Ashish S. Patel, Soundrie Padayachee, Peter Mortimer, Steve Jeffery, Siren Berland, Sahar Mansour, Pia Ostergaard, Taija Makinen, Bijan Modarai, Prakash Saha, Alberto Smith
Summary: The study revealed that mutations in the EPHB4 gene can affect the formation of venous valves, leading to deep venous reflux in patients. Deletion of the Efnb2 gene disrupts normal endothelial expression patterns, affecting the development and proliferation of valve-forming cells.
Article
Genetics & Heredity
Sahar Mansour, Katherine S. Josephs, Pia Ostergaard, Kristiana Gordon, Malou Van Zanten, Julian Pearce, Steve Jeffery, Vaughan Keeley, Katie Riches, Alexander Kreuter, Ulrike Wieland, Rene Haegerling, Lakshmi Ratnam, Ege Sackey, Dionysios Grigoriadis, Bernard Ho, Frances Smith, Elisabeth Rauter, Peter Mortimer, Derek Macallan
Summary: WILD syndrome, previously unrecognized and underestimated, is a generalized primary lymphoedema syndrome. The diagnostic criteria and features have been redefined.
JOURNAL OF MEDICAL GENETICS
(2023)
Article
Multidisciplinary Sciences
Nicola Hellen, Gregory I. Mashanov, Ianina L. Conte, Sophie le Trionnaire, Victor Babich, Laura Knipe, Alamin Mohammed, Kazim Ogmen, Silvia Martin-Almedina, Katalin Torok, Matthew J. Hannah, Justin E. Molloy, Tom Carter
Summary: This study investigates the response of P-selectin to vascular damage. By tracking individual P-selectin molecules, it is found that they initially show fast diffusion but later become increasingly restricted in movement, with around 50% of the molecules becoming completely immobile. Manipulation of the molecule's structure or disruption of the adapter complex can alter its mobility. P-selectin spreads rapidly from sites of exocytosis and then becomes less mobile, which is better suited for its anchoring function.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
Dionysios Grigoriadis, Ege Sackey, Katie Riches, Malou van Zanten, Glen Brice, Ruth England, Mike Mills, Sara E. Dobbins, Li Ling Lee, Steve Jeffery, Liang Dong, David B. Savage, Peter S. Mortimer, Vaughan Keeley, Alan Pittman, Kristiana Gordon, Pia Ostergaard
Summary: Lipoedema is a chronic disorder characterized by excess subcutaneous fat deposition on the lower limbs, mainly affecting women. A study conducted on a UK lipoedema patient cohort identified genetic loci associated with the disease, suggesting a genetic contribution. Replication of the findings in different populations is necessary.
Article
Biochemistry & Molecular Biology
Yann C. Klimentidis, Zhao Chen, Manuel L. Gonzalez-Garay, Dionysios Grigoriadis, Ege Sackey, Alan Pittman, Pia Ostergaard, Karen L. Herbst
Summary: This study used bioelectrical impedance analysis and anthropometric data to identify potential genetic risk factors for lipedema. Genome-wide association study identified several significant loci associated with lipedema, and two of them were replicated in an independent study. Follow-up analyses suggested enrichment of genes expressed in blood vessels and adipose tissue. These findings provide a starting point for better understanding the genetic and physiological basis of lipedema.
EUROPEAN JOURNAL OF HUMAN GENETICS
(2023)
Article
Biochemistry & Molecular Biology
Daniel Greene, Daniela Pirri, Karen Frudd, Ege Sackey, Mohammed Al-Owain, Arnaud P. J. Giese, Khushnooda Ramzan, Sehar Riaz, Itaru Yamanaka, Nele Boeckx, Chantal Thys, Bruce D. Gelb, Paul Brennan, Verity Hartill, Julie Harvengt, Tomoki Kosho, Sahar Mansour, Mitsuo Masuno, Takako Ohata, Helen Stewart, Khalid Taibah, Claire L. S. Turner, Faiqa Imtiaz, Saima Riazuddin, Takayuki Morisaki, Pia Ostergaard, Bart L. Loeys, Hiroko Morisaki, Zubair M. Ahmed, Graeme M. Birdsey, Kathleen Freson, Andrew Mumford, Ernest Turro
Summary: A database containing rare variant genotypes and phenotypes of 77,539 participants sequenced by the 100,000 Genomes Project enables the identification of new disease-causing genes.
Article
Radiology, Nuclear Medicine & Medical Imaging
Michael Mills, Kristiana Gordon, Lakshmi Ratnam, Malou van Zanten, Peter S. Mortimer, Pia Ostergaard, Franklyn A. Howe
Summary: Dynamic contrast-enhanced magnetic resonance lymphangiography (DCE-MRL) is regularly reported as unable to depict lymphatic vessels in healthy limbs. In this study, the researchers aimed to improve lymph vessel conspicuity using registration and subtraction techniques. The results showed that registration and baseline subtraction significantly improved lymphatic visibility in DCE-MRL images.