Autism and Intellectual Disability-Associated KIRREL3 Interacts with Neuronal Proteins MAP1B and MYO16 with Potential Roles in Neurodevelopment

Abstract

Cell-adhesion molecules of the immunoglobulin superfamily play critical roles in brain development, as well as in maintaining synaptic plasticity, the dysfunction of which is known to cause cognitive impairment. Recently dysfunction of KIRREL3, a synaptic molecule of the immunoglobulin superfamily, has been implicated in several neurodevelopmental conditions including intellectual disability, autism spectrum disorder, and in the neurocognitive delay associated with Jacobsen syndrome. However, the molecular mechanisms of its physiological actions remain largely unknown. Using a yeast two-hybrid screen, we found that the KIRREL3 extracellular domain interacts with brain expressed proteins MAP1B and MYO16 and its intracellular domain can potentially interact with ATP1B1, UFC1, and SHMT2. The interactions were confirmed by co-immunoprecipitation and colocalization analyses of proteins expressed in human embryonic kidney cells, mouse neuronal cells, and rat primary neuronal cells. Furthermore, we show KIRREL3 colocalization with the marker for the Golgi apparatus and synaptic vesicles. Previously, we have shown that KIRREL3 interacts with the X-linked intellectual disability associated synaptic scaffolding protein CASK through its cytoplasmic domain. In addition, we found a genomic deletion encompassing MAP1B in one patient with intellectual disability, microcephaly and seizures and deletions encompassing MYO16 in two unrelated patients with intellectual disability, autism and microcephaly. MAP1B has been previously implicated in synaptogenesis and is involved in the development of the actin-based membrane skeleton. MYO16 is expressed in hippocampal neurons and also indirectly affects actin cytoskeleton through its interaction with WAVE1 complex. We speculate KIRREL3 interacting proteins are potential candidates for intellectual disability and autism spectrum disorder. Moreover, our findings provide further insight into understanding the molecular mechanisms underlying the physiological action of KIRREL3 and its role in neurodevelopment.

Dendritic spine actin cytoskeleton in autism spectrum disorder

“…Myosin XVI binds directly to F-actin and also regulates stress fiber remodeling in fibroblasts and neurite outgrowth in neurons via its interaction with phosphatidylinositol 3-kinase (PI3K) and the WAVE complex 129 . Genetic association between the MYO16 gene and autism has been found in two large cohorts (AGRE and ACC) of European ancestry and replicated in two other major cohorts (CAP and CART) 130 , as well as in other studies [131][132][133][134] .…”

Genetic testing including targeted gene panel in a diverse clinical population of children with autism spectrum disorder: Findings and implications

“…Because rare variants in KIRREL3 are not common in any racial/ethnic group (maximum subgroup frequency 3.4%), it seems less likely that racial/ethnic diversity could have affected the interpretation of our results. KIRREL3 encodes one of a group of synaptic cell adhesion molecules (SCAM), functioning to connect pre and postsynapses during the process of synapse formation and maturation via extracellular adhesion domains and signal transduction through a cytoplasmic tail (Baig, Yanagawa, & Tabuchi, ; Liu et al., ). Disruption of KIRREL3 has been reported in patients with neurodevelopmental disorders (Guerin et al., ; Talkowski et al., ), and de novo mutations have been found in whole genome analysis of twins with ASD (Michaelson et al., ).…”

Genetics of Cerebellar and Neocortical Expansion in Anthropoid Primates: A Comparative Approach

“…Several of these genes also showed an association with cerebellum volume in our gene-phenotype association tests at a nominal significance threshold of 0.05. These include AGTPBP1 , the disruption of which causes cerebellar Purkinje cell degeneration [Lalonde et al, 2006], PCNT , which causes primordial dwarfism with microcephaly [Rauch et al, 2008], TH , a gene linked to two disorders that affect motor control, Segawa syndrome and Parkinson's [Ludecke et al, 1995;Haavik and Toska, 1998], and MYO16 and GART which have been putatively linked to autistic spectrum disorders and Down syndrome, respectively [Brodsky et al, 1997;Liu et al, 2015].…”