Citations 2
Ciliopathy patient variants reveal organelle-specific functions for TUBB4B in axonemal microtubules
Dodd, Daniel O , Mechaussier, Sabrina , Yeyati, Patricia L. , McPhie, Fraser , Anderson, Jacob R. , Khoo, Chen Jing , Shoemark, Amelia , Gupta, Deepesh Kumar , Attard, Thomas, Zariwala, Maimoona A. , Legendre, Marie , Bracht, Diana , Gui, Miao , Parry, David , Black, Holly A. , Mitri-Frangieh, Rana, Faucon, Catherine, Kaplan, Josseline, Megaw, Roly , Mohamed, Mai A., Aitken, Stuart , Gautier, Philippe , Reinholt, Finn R., Hirst, Robert A. , O’Callaghan, Chris, Bottier, Mathieu , Escudier, Estelle , Crowley, Suzanne , Descartes, Maria , Kenia, Priti , Amiel, Jeanne , Bacci, Giacomo Maria , Calogero, Claudia , Palazzo, Viviana , Tiberi, Lucia , Blümlein, Ulrike, Rogers, Andrew, Wenger, David A. , Fulton, Anne B. , Rosenfeld, Margaret , Holm, Ingrid A., Quigley, Alan J. , Murphy, Laura C. , Cassidy, Diane M. , Kriegsheim, Alex von , Partnership, Scottish Genomes, Network, Undiagnosed Diseases, Murris, Marlène , Hogg, Claire , Macleod, Kenneth , Urquhart, Don S. , Unger, Stefan , Amselem, Serge , Leigh, Margaret W. , Knowles, Michael R. , Mitchison, Hannah M. , Rozet, Jean‐Michel , Mill, Pleasantine , Gupta, Deepesh K , Wallmeier, Julia , Fassad, Mahmoud R , Tennant, Peter A , Meynert, Alison , Wheway, Gabrielle , Fares-Taie, Lucas , Black, Holly A , Patel, Mitali , McKie, Lisa , Megaw, Roly , Aitken, Stuart , Gautier, Philippe , Heimdal, Ketil , Bottier, Mathieu , Escudier, Estelle , Crowley, Suzanne , Descartes, Maria , Jabs, Ethylin W , Bacci, Giacomo Maria , Calogero, Claudia , Tiberi, Lucia , Wambach, Jennifer A , Wegner, Daniel J , Fulton, Anne B , Kenna, Margaret , Quigley, Alan , Hall, Emma A , Murphy, Laura C , Cassidy, Diane M , von Kriegsheim, Alex , Pasquier, Laurent , Murris, Marlène S , Chalmers, James D , Hogg, Claire , Macleod, Kenneth A , Urquhart, Don S , Unger, Stefan , Aitman, Timothy J , Leigh, Margaret W , Omran, Heymut , Mitchison, Hannah M , Brown, Alan , Marsh, Joseph A , Ti, Shih-Chieh , Horani, Amjad , Rozet, Jean-Michel , Perrault, Isabelle , Mill, Pleasantine , Dodd, Daniel O. , Mechaussier, Sabrina , Gatsogiannis, Christos , Holm, Ingrid A., Partnership, Scottish Genomes, Network, Undiagnosed Diseases, Papon, Jean‐François , Pasquier, Laurent , Chalmers, James D. , Omran, Heymut , Welburn, Julie P. I.
Science | April 25, 2024 | Volume: 384 | Issue: 6694 | Pages: No page available
Tubulin, one of the most abundant cytoskeletal building blocks, has numerous isotypes in metazoans encoded by different conserved genes. Whether these distinct isotypes form cell type– and context-specific microtubule structures is poorly understood. Based on a cohort of 12 patients with primary ciliary dyskinesia as well as mouse mutants, we identified and characterized variants in the TUBB4B isotype that specifically perturbed centriole and cilium biogenesis. Distinct TUBB4B variants differentially affected microtubule dynamics and cilia formation in a dominant-negative manner. Structure-function studies revealed that different TUBB4B variants disrupted distinct tubulin interfaces, thereby enabling stratification of patients into three classes of ciliopathic diseases. These findings show that specific tubulin isotypes have distinct and nonredundant subcellular functions and establish a link between tubulinopathies and ciliopathies.
Biochemical and clinical response after umbilical cord blood transplant in a boy with early childhood‐onset beta‐mannosidosis
Lund, Troy C. , Miller, Weston P. , Eisengart, Julie B. , Simmons, Katrina, Pollard, Laura, Renaud, Deborah L. , Wenger, David A. , Orchard, Paul J. , Patterson, Marc C. , Lund, Troy C , Wegner, Daniel J
Molecular Genetics & Genomic Medicine | May 22, 2019 | Volume: 7 | Issue: 7 | Pages: No page available
Abstract Background Deficiency in the enzyme β‐mannosidase was described over three decades ago. Although rare in occurrence, the presentation of childhood‐onset β‐mannosidase deficiency consists of hypotonia in the newborn period followed by global development delay, behavior problems, and intellectual disability. No effective pharmacologic treatments have been available. Methods We report 2‐year outcomes following the first umbilical cord blood transplant in a 4‐year‐old boy with early childhood‐onset disease. Results We show restoration of leukocyte β‐mannosidase activity which remained normal at 2 years posttransplant, and a simultaneous increase in plasma β‐mannosidase activity and dramatic decrease in urine‐free oligosaccharides were also observed. MRI of the brain remained stable. Neurocognitive evaluation revealed test point gains, although the magnitude of improvement was less than expected for age, causing lower IQ scores that represent a wider developmental gap between the patient and unaffected peers. Conclusion Our findings suggest that hematopoietic cell transplant can correct the biochemical defect in β‐mannosidosis, although preservation of the neurocognitive trajectory may be a challenge.