Title | Recessive Inactivating Mutations in TBCK, Encoding a Rab GTPase-Activating Protein, Cause Severe Infantile Syndromic Encephalopathy. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Chong, JX, Caputo, V, Phelps, IG, Stella, L, Worgan, L, Dempsey, JC, Nguyen, A, Leuzzi, V, Webster, R, Pizzuti, A, Marvin, CT, Ishak, GE, Ardern-Holmes, S, Richmond, Z, Bamshad, MJ, Ortiz-Gonzalez, XR, Tartaglia, M, Chopra, M, Doherty, D |
Corporate Authors | University of Washington Center for Mendelian Genomics |
Journal | Am J Hum Genet |
Volume | 98 |
Issue | 4 |
Pagination | 772-81 |
Date Published | 2016 Apr 07 |
ISSN | 1537-6605 |
Keywords | 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 |
Abstract | 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. |
DOI | 10.1016/j.ajhg.2016.01.016 |
Alternate Journal | Am. J. Hum. Genet. |
PubMed ID | 27040692 |
PubMed Central ID | PMC4833196 |
Grant List | U54 HG006493 / HG / NHGRI NIH HHS / United States U54 HD083091 / HD / NICHD NIH HHS / United States RC2 HG005608 / HG / NHGRI NIH HHS / United States 1RC2HG005608 / HG / NHGRI NIH HHS / United States K12NS049453-09 / NS / NINDS NIH HHS / United States U54HD083091 / HD / NICHD NIH HHS / United States UM1 HG006493 / HG / NHGRI NIH HHS / United States K12 NS049453 / NS / NINDS NIH HHS / United States 1U54HG006493 / HG / NHGRI NIH HHS / United States |