Subtle functional defects in the Arf-specific guanine nucleotide exchange factor IQSEC2 cause non-syndromic X-linked intellectual disability

Abstract

and robert.harvey@pharmacy.ac.uk m utations in IQSEC2, a guanine nucleotide exchange factor for the adp-ribosylation factor (arf) family of small Gtpases have recently been shown to cause non-syndromic x-linked intellectual disability (id), characterised by substantial limitations in intellectual functioning and adaptive behaviour. this discovery was revealed by a combination of large-scale resequencing of the x chromosome, and key functional assays that revealed a reduction, but not elimination, of iqsEc2 GEf activity for mutations affecting conserved amino acids in the iq-like and sec7 domains. compromised Gtp binding activity of iqsEc2 leading to reduced activation of selected arf substrates (arf1, arf6) is expected to impact on cytoskeletal organization, dendritic spine morphology and synaptic organisation. this study highlights the need for further investigation of the iqsEc gene family and arf Gtpases in neuronal morphology and synaptic function, and suggests that the genes encoding the arfGEfs iqsEc1 and iqsEc3 should be considered as candidates for screening in autosomal id. IntroductionIntelligence describes the ability of the brain to comprehend, infer, make decisions, reason, use language, learn and plan. These cognitive abilities require the correct assembly of complex neuronal structures during development and a continued ability to adapt in response to internal and external cues. Disruption of subtle functional defects in the arf-specific guanine nucleotide exchange factor iqsEc2 cause non-syndromic x-linked intellectual disability

Expanding the phenotype of IQSEC2 mutations: truncating mutations in severe intellectual disability

“…They concluded that a loss of GEF activity of IQSEC2 is likely to be the underlying molecular mechanism of ID in patients with IQSEC2 mutations, probably by leading to reduced activation of the ARF6 substrate and influencing the regulation of actin cytoskeleton organisation. 7,8,10 Interestingly, the patient reported by Morleo et al 6 and the three patients reported here presented with features observed in patients with MECP2, FOXG1, CDKL5 and MEF2C mutations (Table 1).…”

“…Shoubridge et al 8 demonstrated that mutation in IQSEC2 leads to significantly diminished GTP binding to ARF6 as compared with the wild types. They concluded that a loss of GEF activity of IQSEC2 is likely to be the underlying molecular mechanism of ID in patients with IQSEC2 mutations, probably by leading to reduced activation of the ARF6 substrate and influencing the regulation of actin cytoskeleton organisation.…”

“…Recently, mutations in IQSEC2 (Sec7 domain of, and IQ-like domain) have been shown to cause nonsyndromic XLID with behavioural disturbance. [5][6][7][8] We report on three male patients with severe syndromic XLID and truncating mutations in IQSEC2.…”

Arfs at a Glance

“…The IQSEC/BRAG Arf GEFs are highly expressed in the postsynaptic density of the central nervous system (Casanova, 2007), and play important roles in signaling during synaptic transmission (Myers et al, 2012). IQSEC2/ BRAG1 is mutated in X-linked nonsyndromic intellectual disability, a form of mental retardation (Shoubridge et al, 2010a;Shoubridge et al, 2010b). Arf proteins and their regulators are hijacked by numerous bacterial and viral pathogens (Dautry-Varsat et al, 2005;Goody and Itzen, 2013;Hsu et al, 2010;Humphreys et al, 2013;Matto et al, 2011).…”

BRAG2/GEP100/IQSec1 Interacts with Clathrin and Regulates α5β1 Integrin Endocytosis through Activation of ADP Ribosylation Factor 5 (Arf5)

“…Additionally, BRAG2 was found to be a major determinant involved in adenocarcinoma invasion, the exact mechanism of which remains elusive but involves a ligand-induced interaction with the EGF receptor and subsequent activation of Arf6 (26). All three BRAGs have been shown to activate Arf6 (7,15,16); however, whether they also act on other Arfs is unknown.…”