X-linked mental retardation: many genes for a complex disorder

Loss-of-function mutation of collybistin is responsible for X-linked mental retardation associated with epilepsy

“…ARHGEF9 encodes collybistin, a brain-specific GEF for the Rho GTPase cell division cycle 42, small Rho-like GTPases, [11][12][13] and it has a pivotal role in the formation of postsynaptic glycine and g-aminobutyric acid receptor clusters. 7 Collybistin has been shown to be expressed in the brain and essential for the gephyrin-dependent clustering of a specific set of g-aminobutyric acid receptors at inhibitory postsynaptic sites, and is also known to affect the plasticity and polarity of the eukaryotic actin cytoskeleton and to alter cell signaling transduction pathways. 9,10,14,15 Figure 3 Sequencing analysis for exon 1a shows a C to T transition at the fourth nucleotide in patient 2, which indicates p.Q2X.…”

Mutations of the UPF3B gene, which encodes a protein widely expressed in neurons, are associated with nonspecific mental retardation with or without autism

“…2 Given that approximately 400 protein coding genes of this chromosome are expressed in the brain, it is likely that several more such genes will be identified. 12,19,20 Finally, the growing number of small chromosomal rearrangements (microdeletion, microduplication) involving one or several genes as identified by array-CGH also suggests that copy number changes are important in XLMR. 5,6,21,22 Among the last new genes found mutated in XLMR, the UPF3B gene has been involved in specific and nonspecific MR with or without autism in 4 of 250 tested families.…”

MECP2 duplications in six patients with complex sex chromosome rearrangements

“…29 Furthermore, cases 5 and 6 have an additional deleted region on Xp, a region known to contain several genes of clinical significance, including SHOX (deletions have been associated with growth retardation) and NLGN4 (mutations have been associated with autism and Asperger syndrome). Interestingly, the deleted region on Xp did not encompass the STS gene in either case 5 or case 6, despite the fact that case 5 exhibited mild ichthyosis of his thighs.…”