Microcephaly, intractable seizures and developmental delay caused by biallelic variants in TBCD: further delineation of a new chaperone-mediated tubulinopathy.
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.
The Institute for Rare Diseases, The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel-Hashomer, Israel.|Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.|The Dr Pinchas Borenstein Talpiot Medical Leadership Program, Sheba Medical Center, Tel-Hashomer, Israel.
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Pode-Shakked
The Institute for Rare Diseases, The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel-Hashomer, Israel.
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Barash
Sheba Cancer Research Center, Sheba Medical Center, Tel-Hashomer, Israel.
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Ziv
Division of Medical Genetics, A.I. duPont Hospital for Children, Wilmington, DE, USA.
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Gripp
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
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Flex
Sheba Cancer Research Center, Sheba Medical Center, Tel-Hashomer, Israel.
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Barel
Section of Pediatric Neurology, St. Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, PA, USA.
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Carvalho
Division of Pediatric Neurology, A.I. duPont Hospital for Children, Wilmington, DE, USA.
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Scavina
SCAI-Super Computing Applications and Innovation Department, CINECA, Rome, Italy.
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Chillemi
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome, Italy.
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Niceta
Sheba Cancer Research Center, Sheba Medical Center, Tel-Hashomer, Israel.
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Eyal
Sheba Cancer Research Center, Sheba Medical Center, Tel-Hashomer, Israel.
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Kol
Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.|Pediatric Neurology Unit, Edmond and Lily Safra Children's Hospital, Tel-Hashomer, Israel.
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Ben-Zeev
Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.|Pediatric Neurology Unit, Edmond and Lily Safra Children's Hospital, Tel-Hashomer, Israel.
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Bar-Yosef
Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.|Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel.
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Marek-Yagel
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome, Italy.
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Bertini
Division of Medical Genetics, A.I. duPont Hospital for Children, Wilmington, DE, USA.
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Duker
Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.|Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel.
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Anikster
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome, Italy.
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Tartaglia
The Institute for Rare Diseases, The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel-Hashomer, Israel.|Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
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Raas-Rothschild
D000818:Animals; D002675:Child, Preschool; D002658:Developmental Disabilities / Q000235:genetics*; D004625:Embryo, Nonmammalian; D004827:Epilepsy / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics; D008279:Magnetic Resonance Imaging; D008297:Male; D008831:Microcephaly / Q000235:genetics*; D008869:Microtubule-Associated Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D008870:Microtubules / Q000235:genetics / Q000473:pathology; D012640:Seizures / Q000000981:diagnostic imaging / Q000235:genetics*; D015027:Zebrafish / Q000196:embryology; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
D008869:Microtubule-Associated Proteins; C418662:TBCD protein, human; C000619704:TBCD protein, zebrafish; D029961:Zebrafish Proteins
TBCD; developmental delay; intractable epilepsy; microcephaly; tubulin