Recessive Inactivating Mutations in TBCK, Encoding a Rab GTPase-Activating Protein, Cause Severe Infantile Syndromic Encephalopathy

Jessica X. Chong, Viviana Caputo, Ian G. Phelps, Lorenzo Stella, Lisa Worgan, Jennifer C. Dempsey, Alina Nguyen, Vincenzo Leuzzi, Richard Webster, Antonio Pizzuti, Colby T. Marvin, Gisele E. Ishak, Simone Ardern-Holmes, Zara Richmond, Michael J. Bamshad, Xilma R Ortiz-Gonzalez, Marco Tartaglia, Maya Chopra, Dan Doherty, University of Washington Center for Mendelian Genomics

Research output: Contribution to journalArticlepeer-review


Infantile encephalopathies are a group of clinically and biologically heterogeneous disorders for which the genetic basis remains largely unknown. Here, we report a syndromic neonatal encephalopathy characterized by profound developmental disability, severe hypotonia, seizures, diminished respiratory drive requiring mechanical ventilation, brain atrophy, dysgenesis of the corpus callosum, cerebellar vermis hypoplasia, and facial dysmorphism. Biallelic inactivating mutations in TBCK (TBC1-domain-containing kinase) were independently identified by whole-exome sequencing as the cause of this condition in four unrelated families. Matching these families was facilitated by the sharing of phenotypic profiles and WES data in a recently released web-based tool (Geno2MP) that links phenotypic information to rare variants in families with Mendelian traits. TBCK is a putative GTPase-activating protein (GAP) for small GTPases of the Rab family and has been shown to control cell growth and proliferation, actin-cytoskeleton dynamics, and mTOR signaling. Two of the three mutations (c.376C>T [p.Arg126(∗)] and c.1363A>T [p.Lys455(∗)]) are predicted to truncate the protein, and loss of the major TBCK isoform was confirmed in primary fibroblasts from one affected individual. The third mutation, c.1532G>A (p.Arg511His), alters a conserved residue within the TBC1 domain. Structural analysis implicated Arg511 as a required residue for Rab-GAP function, and in silico homology modeling predicted impaired GAP function in the corresponding mutant. These results suggest that loss of Rab-GAP activity is the underlying mechanism of disease. In contrast to other disorders caused by dysregulated mTOR signaling associated with focal or global brain overgrowth, impaired TBCK function results in progressive loss of brain volume.

Original languageEnglish
Pages (from-to)772-81
Number of pages10
JournalAmerican Journal of Human Genetics
Issue number4
Publication statusPublished - Apr 7 2016


  • Adolescent
  • Alleles
  • Amino Acid Sequence
  • Brain Diseases
  • Child
  • Child, Preschool
  • Corpus Callosum
  • Female
  • GTPase-Activating Proteins
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Molecular Sequence Data
  • Mutation
  • Pedigree
  • Protein Conformation
  • Protein-Serine-Threonine Kinases
  • Signal Transduction
  • TOR Serine-Threonine Kinases
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't


Dive into the research topics of 'Recessive Inactivating Mutations in TBCK, Encoding a Rab GTPase-Activating Protein, Cause Severe Infantile Syndromic Encephalopathy'. Together they form a unique fingerprint.

Cite this