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

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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 The American Journal of Human Genetics Volume 98, Issue 4, Pages 772-781 (April 2016) DOI: 10.1016/j.ajhg.2016.01.016 Copyright © 2016 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigrees and Pictures of Individuals with TBCK-Related Encephalopathy (A–D) Pedigrees for families A–D (A–D, respectively), in whom loss-of-function mutations in TBCK segregate with disease. Solid black fill indicates individuals affected by TBCK-related encephalopathy. Light blue fill in family B indicates individuals affected by a hematologic phenotype without neurodevelopmental features; neither is homozygous for p.Lys455∗. WES was performed on individuals marked with asterisks. (E–J) Images show the similar facial features and hypotonia in individual A-II-1 at 25 months (E) and 13 years (F), individual B-IV-4 at 17 months (G) and 4 years, 3 months (H), individual B-IV-6 at 18 months (I), individual C-II-1 at 21 months (J), and individual D-II-1 at 14 years. See Table 1 for detailed clinical information on each affected individual and Figure 2 and Table S3 for imaging information. The American Journal of Human Genetics 2016 98, 772-781DOI: (10.1016/j.ajhg.2016.01.016) Copyright © 2016 The American Society of Human Genetics Terms and Conditions

Figure 2 Brain-Imaging Features in Individuals with TBCK-Related Encephalopathy (A–D) Axial T2-weighted (A and C) and sagittal T1-weighted images (B and D) show progressive loss of gray- and white-matter volume (most severe in the frontal lobes), demonstrated by increasing ventriculomegaly and extra-axial spaces (cortical and cerebellar) in individual A-II-1 between 22 days of age (A and B) and 29 months of age (C and D). Also present are swelling of the right parieto-occipital lobe, presumably due to a metabolic stroke (bracket in C), a diffusely thin corpus callosum with absent rostrum (arrowheads in B and D), and mild cerebellar vermis hypoplasia with a relatively spared brainstem. (E and F) Axial T2-weighted (E) and sagittal T1-weighted (F) images show ventriculomegaly, prominent extra-axial spaces, a diffusely thin but complete corpus callosum, and mild cerebellar vermis hypoplasia in individual B-IV-4 at 18 months of age. Right plagiocephaly is also present. (G and H) Axial T2-weighted (G) and sagittal T1-weighted (H) images show marked ventriculomegaly, prominent extra-axial spaces, a diffusely thin but complete corpus callosum, and mild cerebellar vermis hypoplasia in individual B-IV-6 at 6 years of age. Synechiae are also present in the right frontal horn (asterisks in G). (I and J) Axial T1-weighted (I) and sagittal T1-weighted (J) images show ventriculomegaly, prominent extra-axial spaces, a diffusely thin corpus callosum with an absent rostrum and anterior body (arrowhead in J), and mild cerebellar vermis hypoplasia in individual C-II-1 at 21 months of age. (K and L) Axial T2-weighted (K) and sagittal T1-weighted (L) images show mild ventriculomegaly, prominent extra-axial spaces, a diffusely thin corpus callosum, mild cerebellar vermis hypoplasia with a relatively preserved brainstem, and a thick frontal bone (arrow in K) in individual D-II-1 at 14 years of age. The American Journal of Human Genetics 2016 98, 772-781DOI: (10.1016/j.ajhg.2016.01.016) Copyright © 2016 The American Society of Human Genetics Terms and Conditions

Figure 3 Biochemical and Structural Characterization of TBCK Mutations (A) TBCK encodes two isoforms containing a TBC1 domain (TBC) flanked by a rhodanese domain (RHOD) at the C terminus. The long isoform also contains a pseudokinase domain (STYKc) at the N terminus. The location of the identified variants is reported. (B) Western blot shows that TBCK amounts were dramatically lower in a cell line from individual A-II-1 than in two control cell lines. The TBCK monoclonal antibody (1/250, Sigma HPA039951) recognizes a C-terminal fragment of the protein (depicted as a red line in A). After stripping, β-actin (1/5,000, Sigma A5441) was used as a loading control. The predicted sizes of the TBCK long and short isoforms are 101 and 71 kDa, respectively. (C) Conservation of the catalytic arginine “finger” (Arg511 in TBCK) in TBCK orthologs. (D) Homology model of the TBCK TBC1 domain complexed with the Rab33 GTPase. In the overall structure of the complex (left), both proteins are shown in a surface representation; Rab is colored pink, GDP is gray, the TBC1 domain is light blue, and Arg511 is dark blue. In the enlarged view of the active site of the GTPase (right), GDP is reported in gray sticks, and the phosphates are colored orange. AlF3, which in the crystal structure mimics the transition state for GTP hydrolysis, is shown in yellow, and the Mg atom is shown as a purple sphere. The TBC1 domain is reported in ribbon representation, and the side chains of key residues are shown as sticks. The two catalytic “fingers” Arg511 (blue) and Gln546 (green) are shown together with the disease-associated His511, shown in semi-transparent red. The American Journal of Human Genetics 2016 98, 772-781DOI: (10.1016/j.ajhg.2016.01.016) Copyright © 2016 The American Society of Human Genetics Terms and Conditions