title: Recessive Inactivating Mutations in TBCK, Encoding a Rab GTPase-Activating Protein, Cause Severe Infantile Syndromic Encephalopathy.
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.
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Jessica X
authors.initials: JX
authors.lastname: Chong
authors.affiliation: Dipartimento di Medicina Sperimentale, Università La Sapienza, 00161 Rome, Italy.
authors.forename: Viviana
authors.initials: V
authors.lastname: Caputo
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Ian G
authors.initials: IG
authors.lastname: Phelps
authors.affiliation: Dipartimento di Scienze e Tecnologie Chimiche, Università di Roma Tor Vergata, 00133 Rome, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Stella
authors.affiliation: Department of Clinical Genetics, Liverpool Hospital, Liverpool, NSW 2170, Australia.
authors.forename: Lisa
authors.initials: L
authors.lastname: Worgan
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Dempsey
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Alina
authors.initials: A
authors.lastname: Nguyen
authors.affiliation: Dipartimento di Pediatria e di Neuropsichiatria Infantile, Università La Sapienza, 00185 Rome, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Leuzzi
authors.affiliation: T.Y. Nelson Department of Neurology and Neurosurgery and Institute of Neuroscience and Muscle Research, Children's Hospital at Westmead, Westmead, NSW 2145, Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: Webster
authors.affiliation: Dipartimento di Medicina Sperimentale, Università La Sapienza, 00161 Rome, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Pizzuti
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Colby T
authors.initials: CT
authors.lastname: Marvin
authors.affiliation: Department of Radiology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Gisele E
authors.initials: GE
authors.lastname: Ishak
authors.affiliation: T.Y. Nelson Department of Neurology and Neurosurgery and Institute of Neuroscience and Muscle Research, Children's Hospital at Westmead, Westmead, NSW 2145, Australia.
authors.forename: Simone
authors.initials: S
authors.lastname: Ardern-Holmes
authors.affiliation: Department of Genomic Medicine, Royal Prince Alfred Hospital, Missenden Road, Camperdown, Sydney NSW 2050, Australia.
authors.forename: Zara
authors.initials: Z
authors.lastname: Richmond
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Division of Genetic Medicine, Seattle Children's Hospital, Seattle, WA 98105, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bamshad
authors.affiliation: Division of Neurology, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Xilma R
authors.initials: XR
authors.lastname: Ortiz-Gonzalez
authors.affiliation: Area di Ricerca "Genetica e Malattie Rare," Ospedale Pediatrico Bambino Gesù, Istituto di Ricovero e Cura a Carattere Scientifico, 00146 Rome, Italy. Electronic address: marco.tartaglia@opbg.net.
authors.forename: Marco
authors.initials: M
authors.lastname: Tartaglia
authors.affiliation: Department of Genomic Medicine, Royal Prince Alfred Hospital, Missenden Road, Camperdown, Sydney NSW 2050, Australia; Discipline of Genetic Medicine, University of Sydney, Sydney, NSW 2050, Australia; Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, West Gaoke Road, Pudong, Shanghai 200040, China.
authors.forename: Maya
authors.initials: M
authors.lastname: Chopra
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Division of Genetic Medicine, Seattle Children's Hospital, Seattle, WA 98105, USA. Electronic address: ddoher@uw.edu.
authors.forename: Dan
authors.initials: D
authors.lastname: Doherty
mesh_terms: D000293:Adolescent; D000483:Alleles; D000595:Amino Acid Sequence; D001927:Brain Diseases / Q000175:diagnosis / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003337:Corpus Callosum / Q000473:pathology; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D020690:GTPase-Activating Proteins; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; C587598:TBCK protein, human; D058570:TOR Serine-Threonine Kinases
keywords: GTPase-activating protein; Mendelian disease; exome sequencing; infantile encephalopathy; mTOR signaling