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

Am J Hum Genet. 2016 Apr 7;98(4):782-8. doi: 10.1016/j.ajhg.2016.03.016. Epub 2016 Mar 31.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Child
  • Child, Preschool
  • Female
  • Genetic Variation
  • Humans
  • Intellectual Disability / diagnosis
  • Intellectual Disability / genetics*
  • Male
  • Muscle Hypotonia / diagnosis
  • Muscle Hypotonia / genetics*
  • Mutation*
  • Protein Serine-Threonine Kinases / genetics*
  • Racial Groups / genetics
  • Signal Transduction
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • MTOR protein, human
  • Protein Serine-Threonine Kinases
  • TBCK protein, human
  • TOR Serine-Threonine Kinases