Distribution of total brain volume (TBV) and adult self-reported ADHD symptoms in a healthy sample (n = 652).

<p>(<b>a</b>) TBV is associated with the total number of self-reported ADHD symptoms. Of the two ADHD symptom domains, mainly the attentive domain contributes to TBV: (<b>b</b>) inattentive symptoms (β = −.09, <i>p</i>_nominal = .007, <i>p</i>_empirical = .013), and (<b>c</b>) hyperactive/impulsive symptoms (β = −.06, <i>p</i>_nominal = .064, <i>p</i>_emperical = .123). (<b>d</b>) Total brain volume across groups based on the number of self-reported ADHD symptoms. The group with 3 or less self-reported symptoms differed from the intermediate group and from the group with a number of ADHD symptoms corresponding to the ADHD diagnosis (≥6 in either of the two domains). *Total brain volume was adjusted for age, gender and field strength.</p

Additional file 1: Table S1. of Meier-Gorlin syndrome

Proposed guidelines for diagnostic evaluation and management of patients with Meier-Gorlin syndrome based on clinical experience. (DOCX 20 kb

Demographics of the study sample (n = 652).

<p>Subjects were healthy individuals based on self-report.</p

The mammalian Arg/N-end rule pathway and missense mutations in human <i>UBR1</i> that underlie specific cases of the Johanson-Blizzard syndrome (JBS).

<p>(A) The mammalian N-end rule pathway. N-terminal residues are indicated by single-letter abbreviations for amino acids. Yellow ovals denote the rest of a protein substrate. ‘Primary’, ‘secondary’ and ‘tertiary’ denote mechanistically distinct subsets of destabilizing N-terminal residues (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024925#s1" target="_blank">Introduction</a>). C* denotes oxidized Cys, either Cys-sulfinate or Cys-sulfonate. MetAPs, Met-aminopeptidases. (B) Single-residue mutations in the UBR1 proteins of JBS patients #1 and #2. The positions of mutant residues are indicated both for the original mutations in human UBR1 and for their mimics in <i>S. cerevisiae</i>. (C) Same as in B but the mutation in UBR1 of patient #3 (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024925#s2" target="_blank">Results</a>).</p

Functional activity of yeast Ubr1 mimics of missense JBS-UBR1 mutants.

<p>(A) Relative enzymatic activity of βgal in extracts from <i>S. cerevisiae</i> JD55 (<i>ubr1Δ</i>) that expressed His-βgal or Tyr-βgal, and also carried an empty vector, or an otherwise identical plasmid expressing wild-type <i>S. cerevisiae</i> Ubr1, or (separately) its three missense mutants Ubr1^V146L, Ubr1^H160R, or Ubr1^Q1224E. The activity of βgal was measured in triplicates, with standard deviations shown. (B) Relative levels of induction of the peptide transporter Ptr2 were assayed by measuring the activity of a plasmid-borne <i>lacZ</i> (βgal-encoding) reporter that was expressed from the P<i>_PTR2</i> promoter in <i>ubr1Δ S. cerevisiae</i> that carried either an empty vector or otherwise identical plasmids that expressed either wild-type Ubr1 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024925#pone.0024925-Hwang1" target="_blank">[27]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024925#pone.0024925-Xia1" target="_blank">[28]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024925#pone.0024925-Turner1" target="_blank">[52]</a> or its indicated mutants. Cells were grown to A₆₀₀ of ∼0.8 in SC(-Ura, -Leu) medium at 30°C, followed by measurements, in triplicate, of βgal activity in cell extracts, with standard deviations shown. (C) The lysine-requiring JD55 (<i>ubr1Δ</i>) <i>S. cerevisiae</i> strain was grown on plates containing 110 µM lysine (Lys) or 66 µM Lys-Ala dipeptide as the sole source of Lys in the medium <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024925#pone.0024925-Hwang1" target="_blank">[27]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024925#pone.0024925-Hwang3" target="_blank">[33]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024925#pone.0024925-Turner1" target="_blank">[52]</a>. JD52 (<i>ubr1Δ</i>) cells carried a vector plasmid or otherwise identical plasmids expressing wild-type Ubr1 or its missense mutants Ubr1^H160R, Ubr1^V146L and Ubr1^Q1224E. Cells were grown to A₆₀₀ of ∼1 in SC(-Leu) medium at 30°C, washed in sterile water, serially diluted 5-fold, spotted on SC(-Leu, -Lys) plates containing 110 µM Lys or 66 µM Lys-Ala, and incubated at 30°C for 3 days. (D) Cell extracts (equal total protein levels) from experiments described in panels A and B were subjected to SDS-PAGE, followed by immunoblotting with affinity-purified anti-Ubr1 antibody (upper panel) and anti-tubulin antibody (a loading control; lower panel). Asterisk indicates a protein that crossreacts with anti-Ubr1 antibody. (E) Extracts from human lymphocytes (equal amounts of total protein) were subjected to SDS-PAGE, followed by immunoblotting with antibody to human UBR1 (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024925#s4" target="_blank">Materials and Methods</a>). Lane 1, wild-type lymphocytes. Lane 2, same as lane 1 but from lymphocytes of patient #2 (see the main text and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024925#pone-0024925-g001" target="_blank">Figs. 1</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024925#pone-0024925-g002" target="_blank">2</a>). Lane 3, same as lane 1 but with lymphocytes from patient #3. Lane 4, same as lane 1, but with lymphocytes from a JBS patient with a homozygous nonsense mutation in <i>UBR1</i>, previously shown to have no detectable UBR1 (null UBR1 control) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024925#pone.0024925-Varshavsky3" target="_blank">[17]</a>. Lane 5, same as a lane 1.</p

<i>S. cerevisiae</i> Ubr1 N-recognin.

<p>(A) A diagram of the 225 kDa <i>S. cerevisiae</i> Ubr1. The indicated evolutionarily conserved regions of Ubr1 are the UBR box, the BRR (basic residues-rich) domain, the Cys/His-rich RING-H2 domain, and the AI (<u>a</u>uto<u>in</u>hibitory) domain <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024925#pone.0024925-Tasaki1" target="_blank">[18]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024925#pone.0024925-Xie1" target="_blank">[30]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024925#pone.0024925-Hwang3" target="_blank">[33]</a>. Three missense mutations in patients #1-3 of the present work are indicated as well (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024925#pone-0024925-g001" target="_blank">Fig. 1B, C</a>). (B) Ribbon diagram of the <i>S. cerevisiae</i> UBR domain <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024925#pone.0024925-Choi1" target="_blank">[48]</a> in a complex with RLGES, the N-terminal region of the separase-produced fragment of Scc1, a subunit of cohesin <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024925#pone.0024925-Rao1" target="_blank">[75]</a>. The bound RLGES peptide is shown as a stick model, with carbon atoms colored yellow. Several residues are marked with a black sphere and numbered to facilitate the tracing of the polypeptide chain. The names of residues of the RLGES peptide are in red, with the letter ‘s’ (substrate) appended to their position numbers. Side-chains of residues in the UBR domain that are present near JBS mutations (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024925#pone-0024925-g001" target="_blank">Fig. 1B, C</a>) are shown in a stick form, with carbon atoms colored green. Three coordinated zinc ions of the UBR domain <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024925#pone.0024925-Choi1" target="_blank">[48]</a> are shown as red spheres. (C) Close-up view of the UBR region near the V146L mutation (patient #1; <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024925#pone-0024925-g001" target="_blank">Fig. 1B</a>). In panel B, this region of UBR is boxed and labeled as ‘C’. The residues of UBR that accommodate the position-2 Leu residue (‘Leu2s’) of the RLGES peptide substrate are shown and labeled. The van der Waals sphere of the mutant Leu residue, in the UBR1^V146L mutant, is shown as purple dots. (D) Close-up view of the UBR region near the H160R mutation (patient #2, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024925#pone-0024925-g001" target="_blank">Fig. 1B</a>). In panel B, this region of UBR is boxed and labeled as ‘D’. The residues of UBR coordinating Zn3 atom are shown and labeled. The van der Waals sphere of the mutant Arg residue, in the UBR1^H160R mutant, is shown as purple dots. The views in (C) and (D) are oriented to maximize visibility of mutation-proximal residues.</p

Clinical features in JBS patients.

a<p>Ref. 1;</p>b<p>Ref. 6 and unpublished data.</p

Additional file 2: Table S8. of Computer face-matching technology using two-dimensional photographs accurately matches the facial gestalt of unrelated individuals with the same syndromic form of intellectual disability

Concordance between a software-identified top match and whether all three clinical geneticists would have considered this diagnosis based on the image alone. Table S9. Concordance between a software-identified match within the top five closest matches and whether all three clinical geneticists would have considered this diagnosis based on the image alone. Table S10. Concordance between a software-identified match within the top five closest matches and whether all three clinical geneticists would have considered this diagnosis based on the image alone. (DOCX 17 kb

Additional file 1: of Computer face-matching technology using two-dimensional photographs accurately matches the facial gestalt of unrelated individuals with the same syndromic form of intellectual disability

Imagus FRT Algorithm Performancev1.1.BL.pdf. Data on Face Recognition Algorithm Performance on Face Recognition Grand Challenge (FRGC) Benchmark. A license agreement to use FRGC database was obtained. (DOCX 139 kb