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.
Further delineation of the phenotypic spectrum associated with hemizygous loss‐of‐function variants in NONO
Sewani, Maham, Nugent, Kimberly , Blackburn, Patrick R. , Tarnowski, Jessica M., Hernández, Andrés , Amiel, Jeanne , Whalen, Sandra , Keren, Boris , Courtin, Thomas , Yang, Yaping , Pichurin, Pavel N. , Patterson, Marc C. , Scott, Daryl A , Rosenfeld, Jill A. , McLean, Scott
American Journal of Medical Genetics Part A | December 28, 2019 | Volume: 182 | Issue: 4 | Pages: 652-658
AbstractThe non‐POU domain containing, octamer‐binding gene, NONO, is located on chromosome Xq13.1 and encodes a member of a small family of RNA and DNA binding proteins that perform a variety of tasks involved in RNA synthesis, transcriptional regulation and DNA repair. Hemizygous loss‐of‐function variants in NONO have been shown to cause mental retardation, X‐linked, syndromic 34 in males. Features of this disorder can include a range of neurodevelopmental phenotypes, left ventricular noncompaction (LVNC), congenital heart defects, and CNS anomalies. To date only eight cases have been described in the literature. Here we report two unrelated patients and a miscarried fetus with loss‐of‐function variants in NONO. Their phenotypes, and a review of previously reported cases, demonstrate that hemizygous loss‐of‐function variants in NONO cause a recognizable genetic syndrome. The cardinal features of this condition include developmental delay, intellectual disability, hypotonia, macrocephaly, structural abnormalities affecting the corpus callosum and/or cerebellum, LVNC, congenital heart defects, and gastrointestinal/feeding issues. This syndrome also carries an increased risk for strabismus and cryptorchidism and is associated with dysmorphic features that include an elongated face, up/down‐slanted palpebral fissures, frontal bossing, and malar hypoplasia.