Article
Cell Biology
Suzie Buono, Arnaud Monseur, Alexia Menuet, Anne Robe, Catherine Koch, Jocelyn Laporte, Leen Thielemans, Marion Depla, Belinda S. Cowling
Summary: Generating reliable preclinical data in animal models of disease is crucial for therapy development. In this study, statistical analysis and modeling were conducted to predict disease progression, which was then validated using data from a new colony of mice, demonstrating the reproducibility of disease phenotype. Furthermore, the refined phenotypic parameters were used to test the therapeutic efficacy of Dnm2 targeting, showing a significant improvement in disease progression.
DISEASE MODELS & MECHANISMS
(2022)
Article
Multidisciplinary Sciences
Paula Samso, Philipp A. Koch, York Posor, Wen-Ting Lo, Hassane Belabed, Marc Nazare, Jocelyn Laporte, Volker Haucke
Summary: X-linked centronuclear myopathy (XLCNM) is a severe human disease without existing therapies. This study shows that defective focal adhesions and reduced active beta-integrin surface levels in XLCNM can be rescued by loss of PI3KC2 beta function. The researchers also demonstrate the unknown role of PI3KC2 beta in the endocytic trafficking of active beta 1-integrins, providing a potential treatment option for XLCNM patients.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Genetics & Heredity
Adele D'Amico, Antonella Longo, Fabiana Fattori, Michele Tosi, Luca Bosco, Maria Beatrice Chiarini Testa, Giovanna Paglietti, Claudio Cherchi, Adelina Carlesi, Irene Mizzoni, Enrico Bertini
Summary: X-linked myotubular myopathy (XLMTM) is a rare congenital myopathy caused by pathogenic variants in the MTM1 gene. Male patients typically present with severe symptoms at birth, requiring intensive care, and long-term survivors often depend on ventilators and feeding tubes, with possible additional organ involvement. Various therapeutic strategies are being investigated for XLMTM.
ORPHANET JOURNAL OF RARE DISEASES
(2021)
Article
Clinical Neurology
Danielle K. Franken, Karlijn Bouman, Stacha F. I. Reumers, Frederik Braun, Jennifer Spillane, Maartje Pennings, Saskia L. S. Houwen, Corrie E. Erasmus, Ulrike Schara-Schmidt, Erik-Jan Kamsteeg, Heinz Jungbluth, Nicol C. Voermans
Summary: This study investigated the clinical spectrum of neuromuscular features in X-linked myotubular myopathy (XL-MTM) carriers. The results showed that 52% of carriers exhibited muscle weakness, with some cases previously being misclassified. These findings are important for understanding the neuromuscular manifestations of XL-MTM carrier state and for future clinical trials.
Article
Genetics & Heredity
Robert J. Graham, Basil T. Darras, Tmirah Haselkorn, Dan Fisher, Casie A. Genetti, Weston Miller, Alan H. Beggs
Summary: This study analyzed healthcare resource utilization in XLMTM patients within a US medical claims database. The results showed a significant increase in healthcare resource use among XLMTM patients over the past five years. Most patients required respiratory and feeding support and had multiple hospitalizations throughout childhood and beyond.
ORPHANET JOURNAL OF RARE DISEASES
(2023)
Article
Biochemistry & Molecular Biology
Luca Bosco, Daniela Leone, Laura Costa Comellas, Mauro Monforte, Marika Pane, Eugenio Mercuri, Enrico Bertini, Adele D'Amico, Fabiana Fattori
Summary: This study identified a novel MTM1 gene variant in a three-month-old child with XLMTM, which affects the normal splicing process. The researchers expanded the genotypic spectrum of XLMTM and highlighted the importance of sequencing intron-exon boundaries in male patients.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Biochemistry & Molecular Biology
Maria Derkaczew, Piotr Martyniuk, Robert Hofman, Krzysztof Rutkowski, Adam Osowski, Joanna Wojtkiewicz
Summary: Myo-inositol and its derivatives play important roles in intracellular processes and mutations can lead to various disorders. This review provides an in-depth analysis of the influence of phosphatidylinositols and their phosphates on diseases, emphasizing the need for further research on myo-inositol.
Article
Cell Biology
Ege Sarikaya, Nesrin Sabha, Jonathan Volpatti, Emanuela Pannia, Nika Maani, Hernan D. Gonorazky, Alper Celik, Yijng Liang, Paula Onofre-Oliveira, James J. Dowling
Summary: XLMTM is a severe monogenetic disorder of the skeletal muscle caused by mutations in the MTM1 gene. A study of Mtm1 KO mice revealed age-associated changes in gene expression, mitochondrial function, myofiber size, and key molecular markers, providing important insights into the disease pathomechanisms.
DISEASE MODELS & MECHANISMS
(2022)
Article
Immunology
Jeremy S. Tilstra, Minjung Kim, Rachael A. Gordon, Claire Leibler, Haylee A. Cosgrove, Sheldon Bastacky, Kevin M. Nickerson, Mark J. Shlomchik
Summary: Studies have shown that MyD88 in B cells plays a crucial role in the onset and progression of lupus in mice, and its deficiency can improve disease symptoms and reduce autoantibody production. Therefore, targeting MyD88 or its upstream activators may be an effective option for treating lupus.
JOURNAL OF EXPERIMENTAL MEDICINE
(2023)
Review
Biochemistry & Molecular Biology
Raquel Gomez-Oca, Belinda S. Cowling, Jocelyn Laporte
Summary: Centronuclear myopathies (CNM) are rare congenital disorders characterized by muscle weakness and structural defects caused by mutations in genes encoding proteins involved in membrane remodeling, trafficking, and excitation-contraction coupling. Animal models have confirmed shared pathological anomalies in T-tubule remodeling, organelle mispositioning, and protein homeostasis, supporting the development of common therapeutic targets for CNM forms. Promising preclinical results have led to ongoing clinical trials for CNM treatment, including gene therapy and repurposing of existing drugs.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Medicine, Research & Experimental
Sophie Karolczak, Ashish R. Deshwar, Evangelina Aristegui, Binita M. Kamath, Michael W. Lawlor, Gaia Andreoletti, Jonathan Volpatti, Jillian L. Ellis, Chunyue Yin, James J. Dowling
Summary: In this study, liver abnormalities associated with X-Linked Myotubular Myopathy (XLMTM) were observed in a zebrafish model, providing new insights into the understanding and comprehensive treatment of this human disease.
JOURNAL OF CLINICAL INVESTIGATION
(2023)
Article
Clinical Neurology
Jonathan R. Volpatti, Mehdi M. Ghahramani-Seno, Melanie Mansat, Nesrin Sabha, Ege Sarikaya, Sarah J. Goodman, Eric Chater-Diehl, Alper Celik, Emanuela Pannia, Carine Froment, Lucie Combes-Soia, Nika Maani, Kyoko E. Yuki, Gaetan Chicanne, Liis Uuskula-Reimand, Simon Monis, Sana Akhtar Alvi, Casie A. Genetti, Bernard Payrastre, Alan H. Beggs, Carsten G. Bonnemann, Francesco Muntoni, Michael D. Wilson, Rosanna Weksberg, Julien Viaud, James J. Dowling
Summary: In this study, we identified valproic acid as a potential therapy for XLMTM through drug screening in zebrafish and mouse models. We found that valproic acid suppresses the disease phenotype by inhibiting HDAC and normalizing DNA methylation. Additionally, we discovered a unique DNA methylation signature in XLMTM patients, suggesting that epigenetic alterations could be targeted for therapeutic intervention.
ACTA NEUROPATHOLOGICA
(2022)
Article
Clinical Neurology
Silvia Nitschke, Mitchell A. Sullivan, Sharmistha Mitra, Charlotte R. Marchioni, Jennifer P. Y. Lee, Brandon H. Smith, Saija Ahonen, Jun Wu, Erin E. Chown, Peixiang Wang, Sara Petkovic, Xiaochu Zhao, Laura F. DiGiovanni, Ami M. Perri, Lori Israelian, Tamar R. Grossman, Holly Kordasiewicz, Francisco Vilaplana, Kazuhiro Iwai, Felix Nitschke, Berge A. Minassian
Summary: This study investigates the influence of glucan chain length on precipitation and the disease caused by abnormal glycogen structure. The authors found that the glycogen pathology of RBCK1 deficiency is similar to malin-deficient Lafora disease and can be rescued by downregulating glycogen synthase.
Article
Pharmacology & Pharmacy
Charlotte Gineste, Jocelyn Laporte
Summary: Congenital myopathies are rare and severe genetic diseases that affect the skeletal muscle function in children and adults. Various subgroups exist based on clinical and histopathological features. Currently, there are no approved treatments for any congenital myopathies. However, there are ongoing research efforts to explore pharmacological and genetic-based therapeutic approaches.
CURRENT OPINION IN PHARMACOLOGY
(2023)
Article
Oncology
Takuji Iwase, Shigehira Saji, Kotaro Iijima, Kenji Higaki, Shoichiro Ohtani, Yasuyuki Sato, Yasuo Hozumi, Yoshie Hasegawa, Yasuhiro Yanagita, Hiroyuki Takei, Maki Tanaka, Hideji Masuoka, Masahiko Tanabe, Chiyomi Egawa, Yoshifumi Komoike, Toshitaka Nakamura, Hiroshi Ohtsu, Hirofumi Mukai
Summary: This study investigated the effects of extending the treatment with an aromatase inhibitor for 10 years on disease-free survival in postmenopausal hormone receptor-positive breast cancer patients. The results showed that extending the treatment with an aromatase inhibitor for an additional 5 years improved disease-free survival.
JOURNAL OF CLINICAL ONCOLOGY
(2023)