Figure 4
From: X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes
Novel X-linked intellectual disability (XLID) genes and candidates that emerged from this study encode components of key cellular protein networks. All available protein–protein interactions involving known intellectual disability (ID) proteins and the proteins likely implicated in XLID identified in this study were first extracted from the literature and then connected into a set of protein–protein interaction networks via the Ingenuity tool. Functional cellular subnetworks were extracted by using the available annotations of the interacting proteins (e.g., defined by functional category ‘translation/transcription’) and by performing literature searches. (a) PSD-95 (postsynaptic density protein 95)/Ras/Rho interaction network. CNKSR2 (CNK2, MAGUIN1, validated XLID protein) that likely functions as an adapter protein or regulator of Ras signaling pathways interacts with PSD-95 in synaptosomes.122 FRMPD4 (Preso, validated XLID protein), which is a positive regulator of dendritic spine morphogenesis and density and is required for the maintenance of excitatory synaptic transmission, interacts with PSD-95,104 and together with its binding partner ARHGEF7 (βPix) localizes in dendritic growth cones.123 (b) Transcriptional/translational interaction network. Known protein complexes are highlighted. RNA Polymerase II (RNAPII) complex with the core component TAF1 (novel candidate XLID protein). ATN1 (known ID protein) interacts with TAF4 and negatively regulates transcription of RNAPII.124 Large ribosomal subunit (60S) contains RPL10 (known candidate XLID/autism protein). LAS1L (novel XLID protein) is essential for the biogenesis of the ribosomal subunit 60S.114 Eukaryotic translation initiation factor, EIF2S3 (novel XLID protein), is a component of the translation initiation complex and promotes binding of the initiator methionyl-tRNA to the 40S ribosomal subunit.125 POLDIP3 (SKAR), involved in positive regulation of translation, associates with THOC2 (novel XLID protein) as a part of the TREX complex (functioning in mRNA export),126 with mRNA surveillance factor UPF3B (known XLID protein), as well as with a core component of the exon junction complex, EIF4A3.127 CDK16 (novel candidate XLID protein) and Synapsin 1 (Syn1, known XLID protein) were shown to interact in a membrane fraction from brain.71 Cdk16 associates with 14-3-3 zeta in Neuro-2A cells.69 Mediator complex, which functions as a transcriptional coactivator, contains MED12 (known XLID protein) and MED13L (known ID protein). NIPBL (known ID protein) is involved in loading of cohesin and associates with the mediator-cohesin complex, which interfaces gene expression and chromatin structure. Histone methyltransferase MLL2 (known ID protein) associates with a core component of Pol II, POLR2B, and activates transcription.128 Deubiquitinating enzyme USP27X (novel XLID protein) interacts with USP22 that is required for histone deubiquitination,129 and which associates together with TAF10 as part of the TBP-free TAF complex (TFTC).109 ADRA2B, G-protein coupled receptor, by interacting with EIF2B130 and 14-3-3 zeta131 links G protein-mediated signaling network and cellular control of protein synthesis. (c) Ubiquitination interaction network. KLHL15 (validated XLID protein) with a function in protein ubiquitination interacts with a component of an ubiquitin E3 ligase, CUL3.132 RLIM (novel XLID protein) is an E3 ubiquitin protein ligase113 and associates with UBE2D1.133
