Microcephaly,intractable seizures and developmental delay caused by biallelic variants in TBCD: further delineation of a new chaperone‐mediated tubulinopathy |
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| Authors: | K.W. Gripp E. Flex O. Barel K.S. Carvalho M. Scavina G. Chillemi M. Niceta E. Eyal N. Kol B. Ben‐Zeev O. Bar‐Yosef D. Marek‐Yagel E. Bertini A.L. Duker Y. Anikster M. Tartaglia A. Raas‐Rothschild |
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| Affiliation: | 1. Division of Medical Genetics, A.I. duPont Hospital for Children, Wilmington, DE, USA;2. Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy;3. Sheba Cancer Research Center, Sheba Medical Center, Tel‐Hashomer, Israel;4. Section of Pediatric Neurology, St. Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, PA, USA;5. Division of Pediatric Neurology, A.I. duPont Hospital for Children, Wilmington, DE, USA;6. SCAI‐Super Computing Applications and Innovation Department, CINECA, Rome, Italy;7. Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome, Italy;8. Sackler Faculty of Medicine, Tel‐Aviv University, Tel‐Aviv, Israel;9. Pediatric Neurology Unit, Edmond and Lily Safra Children's Hospital, Tel‐Hashomer, Israel;10. Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel‐Hashomer, Israel;11. Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome, ItalyThese authors contributed equally as the senior investigators in this project.;12. The Institute for Rare Diseases, The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel‐Hashomer, Israel;13. Sackler Faculty of Medicine, Tel‐Aviv University, Tel‐Aviv, IsraelThese authors contributed equally as the senior investigators in this project. |
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| Abstract: | Microtubule dynamics play a crucial role in neuronal development and function, and several neurodevelopmental disorders have been linked to mutations in genes encoding tubulins and functionally related proteins. Most recently, variants in the tubulin cofactor D (TBCD) gene, which encodes one of the five co‐chaperones required for assembly and disassembly of α/β‐tubulin heterodimer, were reported to underlie a recessive neurodevelopmental/neurodegenerative disorder. We report on five patients from three unrelated families, who presented with microcephaly, intellectual disability, intractable seizures, optic nerve pallor/atrophy, and cortical atrophy with delayed myelination and thinned corpus callosum on brain imaging. Exome sequencing allowed the identification of biallelic variants in TBCD segregating with the disease in the three families. TBCD protein level was significantly reduced in cultured fibroblasts from one patient, supporting defective TBCD function as the event underlying the disorder. Such reduced expression was associated with accelerated microtubule re‐polymerization. Morpholino‐mediated TBCD knockdown in zebrafish recapitulated several key pathological features of the human disease, and TBCD overexpression in the same model confirmed previous studies documenting an obligate dependency on proper TBCD levels during development. Our findings confirm the link between inactivating TBCD variants and this newly described chaperone‐associated tubulinopathy, and provide insights into the phenotype of this disorder. |
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| Keywords: | developmental delay intractable epilepsy microcephaly TBCD tubulin |
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