Mutations in TBCK, Encoding TBC1-Domain-Containing Kinase, Lead to a Recognizable Syndrome of Intellectual Disability and Hypotonia - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue American Journal of Human Genetics Année : 2016

Mutations in TBCK, Encoding TBC1-Domain-Containing Kinase, Lead to a Recognizable Syndrome of Intellectual Disability and Hypotonia

Dong Li
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Margaret Harr
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Shimon Edvardson
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Elizabeth Chisholm
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Ganka Douglas
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Maria Guillen Sacoto
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Abdelkrim Saadi
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Alekhya Narravula
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Maria Walke
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Peter Horner
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Peter Day-Salvatore
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Parul Jayakar
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Samantha Vergano
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Madhuri Hegde
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Laurence Colleaux
Peter Crino
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Hakon Hakonarson
Elizabeth j. Bhoj
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Maria j. Guillen Sacoto
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Michele b. Horner
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Debra-Lynn Day-Salvatore
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Samantha a. schrier Vergano
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Mark a. Tarnopolsky
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Résumé

Through an international multi-center collaboration, 13 individuals from nine unrelated families and affected by likely pathogenic biallelic variants in TBC1-domain-containing kinase (TBCK) were identified through whole-exome sequencing. All affected individuals were found to share a core phenotype of intellectual disability and hypotonia, and many had seizures and showed brain atrophy and white-matter changes on neuroimaging. Minor non-specific facial dysmorphism was also noted in some individuals, including multiple older children who developed coarse features similar to those of storage disorders. TBCK has been shown to regulate the mammalian target of rapamycin (mTOR) signaling pathway, which is also stimulated by exogenous leucine supplementation. TBCK was absent in cells from affected individuals, and decreased phosphorylation of phospho-ribosomal protein S6 was also observed, a finding suggestive of downregulation of mTOR signaling. Lastly, we demonstrated that activation of the mTOR pathway in response to L-leucine supplementation was retained, suggesting a possible avenue for directed therapies for this condition.

Dates et versions

hal-02087858 , version 1 (02-04-2019)

Identifiants

Citer

Elizabeth J. Bhoj, Dong Li, Margaret Harr, Shimon Edvardson, Orly Elpeleg, et al.. Mutations in TBCK, Encoding TBC1-Domain-Containing Kinase, Lead to a Recognizable Syndrome of Intellectual Disability and Hypotonia. American Journal of Human Genetics, 2016, 98 (4), pp.782-788. ⟨10.1016/j.ajhg.2016.03.016⟩. ⟨hal-02087858⟩
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