title: 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.
authors.affiliation: J.C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, South Carolina, United States of America.
authors.forename: Ying F
authors.initials: YF
authors.lastname: Liu
authors.affiliation: J.C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, South Carolina, United States of America.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Sowell
authors.affiliation: J.C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, South Carolina, United States of America.
authors.forename: Yue
authors.initials: Y
authors.lastname: Luo
authors.affiliation: J.C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, South Carolina, United States of America.
authors.forename: Alka
authors.initials: A
authors.lastname: Chaubey
authors.affiliation: Department of Medicine, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Cameron
authors.affiliation: Department of OB/GYN, Institute of Molecular Medicine and Genetics, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Hyung-Goo
authors.initials: HG
authors.lastname: Kim
authors.affiliation: J.C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, South Carolina, United States of America; Department of Genetics and Biochemistry, Clemson University, Clemson, South Carolina, United States of America.
authors.forename: Anand K
authors.initials: AK
authors.lastname: Srivastava
mesh_terms: D000293:Adolescent; D000818:Animals; D000067877:Autism Spectrum Disorder / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005260:Female; D018507:Gene Expression Regulation, Developmental; D012696:Glycine Hydroxymethyltransferase; D006056:Golgi Apparatus / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000235:genetics* / Q000378:metabolism; D009218:Myosins / Q000235:genetics* / Q000378:metabolism; D055495:Neurogenesis / Q000235:genetics*; D009473:Neuronal Plasticity / Q000235:genetics; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D061251:Primary Cell Culture; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D015398:Signal Transduction; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics / Q000378:metabolism; D013572:Synaptic Vesicles / Q000235:genetics / Q000378:metabolism; D020798:Two-Hybrid System Techniques; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism
chemical_list: C503551:ATP1B1 protein, human; D002352:Carrier Proteins; C470936:KIRREL3 protein, human; C475491:MAP1B protein, human; C000606501:MYO16 protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; C502096:UFC1 protein, human; D012696:Glycine Hydroxymethyltransferase; C520541:SHMT protein, human; D044763:Ubiquitin-Conjugating Enzymes; D018995:Myosin Heavy Chains; D009218:Myosins; D000254:Sodium-Potassium-Exchanging ATPase