Haploinsufficiency in the ANKS1B gene encoding AIDA-1 leads to a neurodevelopmental syndrome

Abstract

Neurodevelopmental disorders, including autism spectrum disorder, have complex polygenic etiologies. Single-gene mutations in patients can help define genetic factors and molecular mechanisms underlying neurodevelopmental disorders. Here we describe individuals with monogenic heterozygous microdeletions in ANKS1B , a predicted risk gene for autism and neuropsychiatric diseases. Affected individuals present with a spectrum of neurodevelopmental phenotypes, including autism, attention-deficit hyperactivity disorder, and speech and motor deficits. Neurons generated from patient-derived induced pluripotent stem cells demonstrate loss of the ANKS1B -encoded protein AIDA-1, a brain-specific protein highly enriched at neuronal synapses. A transgenic mouse model of Anks1b haploinsufficiency recapitulates a range of patient phenotypes, including social deficits, hyperactivity, and sensorimotor dysfunction. Identification of the AIDA-1 interactome using quantitative proteomics reveals protein networks involved in synaptic function and the etiology of neurodevelopmental disorders. Our findings formalize a link between the synaptic protein AIDA-1 and a rare, previously undefined genetic disease we term ANKS1B haploinsufficiency syndrome.

Autism spectrum disorder-like behavior caused by reduced excitatory synaptic transmission in pyramidal neurons of mouse prefrontal cortex

“…Three chamber sociality test. The three-chamber sociality test was adapted from Yang et al [78][79][80][81] . A three-chamber apparatus (50 × 42 cm, equipped with dividing walls with doorway (13 cm width) which enable mice to access each chamber) was used.…”

“…The time for the test mouse to be facing and sniffing the novel mouse containing cage (T-mouse) and that for the test mouse to be facing and sniffing the novel object containing cage (T-object) were measured by an observer who remained blind to the experimental conditions of the test mouse (with or without knockdown) throughout analysis. The sociality index [78][79][80] Reciprocal social interaction test. For the reciprocal social interaction test 10 , mice were placed in the corner of an open field (50 × 40 × 50 cm, 15 lux) and adult male DBA2 mice (SLC JAPAN) were placed in the opposite corner.…”

Comparing synaptic proteomes across seven mouse models for autism reveals molecular subtypes and deficits in Rho GTPase signaling

“…ANKS1B was previously identified in ASD risk gene networks (Li et al 2014), and we found that its product AIDA-1 regulates activity-induced protein synthesis (Jordan et al 2007), hippocampal synaptic plasticity (Tindi et al 2015), and NMDA receptor subunit composition (Tindi, et al 2015; Carbonell, et al 2019). AIDA-1 is a core protein of the postsynaptic density and interacts with PSD95 in a complex that contains other factors associated with neurodevelopmental disorders, including Grin2b, Syngap1 , and Nlgn s (Carbonell, et al 2019; Kaizuka and Takumi 2018). These findings support the idea that molecular mechanisms regulating synaptic function underlie ASD pathobiology (Bourgeron 2015; Zoghbi and Bear 2012).…”

“…Non-syndromic ASD models, such as those induced by valproic acid or maternal immune activation, also reveal structural and functional synaptic deficits, showing that environmental factors can lead to similar synaptic phenotypes (Andoh et al 2019; Cellot et al 2016; Li et al 2018; Martin and Manzoni 2014; Patrich et al 2016; Sui and Chen 2012; Wang et al 2018). We recently developed a mouse model for ANKS1B haploinsufficiency, a rare genetic syndrome of ASD and other neurodevelopmental disorders caused by loss of the ANKS1B gene (Carbonell et al 2019). ANKS1B was previously identified in ASD risk gene networks (Li et al 2014), and we found that its product AIDA-1 regulates activity-induced protein synthesis (Jordan et al 2007), hippocampal synaptic plasticity (Tindi et al 2015), and NMDA receptor subunit composition (Tindi, et al 2015; Carbonell, et al 2019).…”

“…We recently developed a mouse model for ANKS1B haploinsufficiency, a rare genetic syndrome of ASD and other neurodevelopmental disorders caused by loss of the ANKS1B gene (Carbonell et al 2019). ANKS1B was previously identified in ASD risk gene networks (Li et al 2014), and we found that its product AIDA-1 regulates activity-induced protein synthesis (Jordan et al 2007), hippocampal synaptic plasticity (Tindi et al 2015), and NMDA receptor subunit composition (Tindi, et al 2015; Carbonell, et al 2019). AIDA-1 is a core protein of the postsynaptic density and interacts with PSD95 in a complex that contains other factors associated with neurodevelopmental disorders, including Grin2b, Syngap1 , and Nlgn s (Carbonell, et al 2019; Kaizuka and Takumi 2018).…”