Dedicator of cytokinesis 8 is disrupted in two patients with mental retardation and developmental disabilities

Abstract

We have identified disruptions in the dedicator of cytokinesis 8 gene, DOCK8, in two unrelated patients with mental retardation (MR). In one patient, a male with MR and no speech, we mapped a genomic deletion of approximately 230 kb in subtelomeric 9p. In the second patient, a female with mental retardation and ectodermal dysplasia and a balanced translocation, t(X;9) (q13.1;p24), we mapped the 9p24 breakpoint to a region overlapping with the centromeric end of the 230-kb subtelomeric deletion. We characterized the DOCK8 gene from the critical 9p deletion region and determined that the longest isoform of the DOCK8 gene is truncated in both patients. Furthermore, the DOCK8 gene is expressed in several human tissues, including adult and fetal brain. Recently, a role for DOCK8 in processes that affect the organization of filamentous actin has been suggested. Several genes influencing the actin cytoskeleton have been implicated in human cognitive function and thus a possibility exists that the rare mutations in the DOCK8 gene may contribute to some cases of autosomal dominant mental retardation.

Mice with mutations of Dock7 have generalized hypopigmentation and white-spotting but show normal neurological function

“…The closely related protein DOCK6 has also been shown to interact with Racs, as well as Cdc42, and to function in neurite growth (35). Moreover, mutations in DOCK8 have been found in patients with mental retardation and developmental disabilities (36). The participation of other GEFs and other Rho family GTPases in neurodevelopment may compensate for DOCK7 deficiency.…”

The Atypical Guanine Nucleotide Exchange Factor Dock4 Regulates Neurite Differentiation through Modulation of Rac1 GTPase and Actin Dynamics

“…For instance, Dock1 (Dock180) regulates axon pathfinding and spine morphogenesis (6,7), Dock3 is important for axonal growth and survival (8), and Dock7 regulates neuronal polarization and cortical neurogenesis (9,10). Moreover, members of Dock, including Dock3, Dock8, and Dock9, have been found to be associated with neurodegenerative and neuropsychiatric diseases (11)(12)(13)(14)(15). These lines of evidence highlight a pivotal role of the Dock family during normal neuronal development and brain functioning.…”

Complex rearrangement involving 9p deletion and duplication in a syndromic patient: Genotype/phenotype correlation and review of the literature

“…Loss or mutation of a few genes such as DOCK8, KANK1(ANKRD15), SLC1A1 and GLDC, has been already associated with mental, motor retardation and/or other neurological symptoms (Bailey et al, 2011;Griggs et al, 2008;Lerer et al, 2005;Meyer et al, 2010), making their deletion likely responsible for the severe mental and motor delay of our patient. At least 120 genes are located in the duplicated regions of our patient and some may be dosage-sensitive thus contributing to the observed phenotype.…”