A Truncating Mutation of TRAPPC9 Is Associated with Autosomal-Recessive Intellectual Disability and Postnatal Microcephaly Ganeshwaran H. Mochida, Muhammad.

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A Truncating Mutation of TRAPPC9 Is Associated with Autosomal-Recessive Intellectual Disability and Postnatal Microcephaly Ganeshwaran H. Mochida, Muhammad Mahajnah, Anthony D. Hill, Lina Basel-Vanagaite, Danielle Gleason, R. Sean Hill, Adria Bodell, Moira Crosier, Rachel Straussberg, Christopher A. Walsh The American Journal of Human Genetics Volume 85, Issue 6, Pages 897-902 (December 2009) DOI: 10.1016/j.ajhg.2009.10.027 Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 1 Brain MRI of a Patient with a TRAPPC9 Mutation (A) T1-weighted axial image of Patient 2 (MC-6102) reveals microcephaly but a normal gyral pattern of the cerebral cortex. The cerebral white matter is reduced. Scale bar is 2 cm for all images. (B) T1-weighted sagittal image of the same patient is remarkable for a thin but fully formed corpus callosum and mild hypoplasia of the inferior cerebellar vermis. (C) T1-weighted axial image of an age-matched control individual. (D) T1-weighted sagittal image of an age-matched control individual. The American Journal of Human Genetics 2009 85, 897-902DOI: (10.1016/j.ajhg.2009.10.027) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 2 Mapping and Cloning of the Causative Gene (A) Pedigree and haplotype of the distal chromosome 8 of the family studied. There is an area of shared homozygosity in all three affected children (box). This identified the candidate region as defined by markers D8S272 and D8S1744. (B) A graph showing multipoint LOD scores of the same region of chromosome 8. LOD scores above 3.0 were achieved between D8S272 and D8S1744. (C) Sequencing of candidate genes within the interval revealed a nonsense nucleotide change in the exon 7 of the TRAPPC9 gene. The C to T change (arrow) in patients creates a stop codon (red shaded box) and is expected to result in R to X change on the amino acid level. (D) Western blot analysis of the lymphoblasts from the patients and control individuals. A single band was detected by Trappc9 antibody (green) in protein extracts from three different control lymphoblasts (C1, C2, and C3). This band was not detected in lymphoblast extracts from Patient 1 or Patient 2 (P1 and P2, respectively), despite the fact that a higher amount of protein was loaded compared to the control samples. Red represents a loading control (β-actin). The American Journal of Human Genetics 2009 85, 897-902DOI: (10.1016/j.ajhg.2009.10.027) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 3 In Situ Hybridization and Immunofluorescence Studies of TRAPPC9 in the Developing Mouse and Human Brain (A) In E14 mouse brain, a low level of Trappc9 RNA expression was seen throughout the cerebral mantle (scale bar in [A]–[H] = 100 μm). (B) In P0 mouse brain, there was a slightly higher level of RNA expression in the cerebral mantle, with the exception of the developing white matter, which is devoid of staining. (C) In adult mouse cerebral cortex, there is a moderate to high level of RNA expression in cortical neurons of all layers. (D) In human brain at 11.5 weeks, a moderate level of TRAPPC9 RNA expression is seen in the cortical plate. (E) In E15 mouse brain, Trappc9 protein could be detected throughout the cerebral cortex, with increased accumulation in the cortical plate. (F) In P3 mouse brain, Trappc9 protein was detected in the cell bodies of cortical plate neurons and in cells within the subventricular zone. (G) Neuronal accumulation of Trappc9 continued in the P8 cerebral cortex, with higher levels of signal in the large pyramidal neurons of layer V. (H) Trappc9 immunofluorescence persisted in adult mouse cortical neurons. (I) Confocal microscopy of mouse cortical plate revealed distinct subcellular locations for Trappc9 (red) and the Golgi apparatus marker GM130 (green) (scale bar in [I]–[K] = 10 μm). (J) Trappc9 (red) did not colocalize with Rab7 (green), a marker of late endosomes and lysosomes. (K) Trappc9 (red) did not colocalize with transferrin receptor (green), a marker for early endosomes. The American Journal of Human Genetics 2009 85, 897-902DOI: (10.1016/j.ajhg.2009.10.027) Copyright © 2009 The American Society of Human Genetics Terms and Conditions