Figure 1. Positions of the genes associated with syndromic forms of X-linked mental retardation (MRXS) are indicated on the left. Mutant phenotypes are classified as metabolic disorders (bold type), disorders of morphogenesis (italic) or neuromuscular disorders (roman). Genes involved in nonsyndromic X-linked mental retardation (MRX) are shown on the right. The question marks indicate that these genes are strong candidates to cause mental retardation, although mutations in these genes have not yet been identified. Genes associated only with nonsyndromic MR are underlined. ABCD1: ATP-binding cassette, subfamily D, member 1; ATP7A: ATPase,  Cu²⁺-transporting -polypetide; ATRX: thalassemia/mental retardation syndrome, X-linked; ARHGEF6: Rac/Cdc42 guanine nucleotide exchange factor (GEF) 6; CXORF5: chromosome X open reading frame; DCX: doublecortex, lissencephaly, X-linked (doublecortin); FGD1: faciogenital dysplasia; FLN1: filamin A, -lactin-binding-protein-280; FMR1: fragile X mental retardation; GPC3: glypican 3; HPRT: hypoxanthine phosphoribosyltransferase 1; IL1RAPL1: IL-1 receptor accessory protein-like 1; GDI1: (GDI), Rab GDP dissociation inhibitor 1; IDS: iduronate 2-sulfatase; LAMP2: lysosome-associated membrane protein 2; L1CAM: L1 cell adhesion molecule; MECP2: methyl CpG-binding protein 2; NXF5: nuclear export factor 5; MID1: midline 1; OPHN1: oligophrenin 1; PAK3: p21 activated kinase 3; PLP: proteolipid protein 1; RSK2 (RPS6KA3): ribosomal protein S6 kinase polypeptide 3; RSK4 (RPS6KA6): ribosomal protein S6 kinase polypeptide 6; SLC6A8: solute carrier family 6, member 8; TIMM8A: translocase of inner mitochondrial membrane 8; TM4SF4: Xp11.4 tetraspanin, transmembrane 4 superfamily member 2; VCXA: variable charged, X chromosome mRNA on CRI-S232A.

Figure 2. (a) Genes/proteins (ARHGEF6, OPHN1, PAK3, TM4SF4) involved in the pathogenesis of X-linked mental retardation and their functional context in signal transduction pathways. The activation of the small GTPases Ras, Rac, Cdc42 is dependent on diverse signals mediated by lipids or growth factors and their receptors. Activated Rho, Rac and Cdc42 GTPases are involved in the formation of lamellipodia, filopodia, stress fibers and in signal transmission via focal adhesions. In neuronal cells, these processes influence axon growth and dendrite plasticity. JNK: c-jun N-terminal kinase; PIX: PAK-interacting exchange factor; arrows indicate activating influences; dotted arrows represent simplification of downstream pathways leading to the indicated effects. (b) Involvement of RabGDI (GDP dissociation inhibitor) in Rab cycling. RabGTPase bound to GDP is retrieved from the target membrane of an organelle or vesicle by GDI, and maintained in this inactive state in the cytosol. Subsequently, GDI is able to deliver RapGDP back to the donor membrane, where GDI dissociates from the complex and a GEF regulates GDP replacement by GTP. In its active, GTP-bound, state, Rab acts on effector proteins. Following conversion of the GTP-bound state to the GDP-bound form, during or after vesicle fusion and neurotransmitter release, GDI retrieves RabGDP to the cytosolic pool.