Author:

Keywords:

Autism, Neurobeachin, rugose, genetics, Drosophila

Abstract:

Autism Spectrum Disorders (ASD) are a group of developmental disorders o f the central nervous system characterized by impairments in social inte raction, communication and restricted repetitive and stereotyped be havior. There is a large phenotypic heterogeneity and diagnosis is solel y based on the observation of behavior and cognitive phenotypes.&nb sp;It is generally assumed that ASD has a polygenic cause, but the patho genic mechanism is still unknown. Boys are four times more affected than girls.Amisyn, SCAMP5 and neurobeachin ( NBEA) were identified as candidate genes for ASD in patients with a de novo chromosomal rearrangement and a family history nega tive for ASD. For amisyn and SCAMP5 the expression level was affected due to the nearby breakpoint whereas the NBE A gene was disrupted. Three other patients with ASD are carrier of a monoallelic deletion of NBEA. All three genes have a presumed function in vesicle transport and are negative regulators of large dens e-core vesicle secretion in a neuroendocrine cell line. In order to addr ess the frequency of genomic aberrations for these genes in the autistic population, amisyn and SCAMP5 were sequenced and the presence of CNVs was assessed for NBEA. However, no addit ional aberrations were identified.NBEA is a multidomain scaffolding protein with a presumed function in post-Golgi vesicle traffi cking. Nbea knockout mice die immediately after birth because they fail to initiate respiration. They have a blocked evoked synaptic transmission at the neuromuscular junction and synapses in the brainstem show an impairment in inhibitory and excitatory neurotransmission. Like for other BEACH-family members, the exact function of NBEA is currently unknown. Rugose, the putative homolog of NBEA in Drosophila mel anogaster, was used to further study Nbea function. Rugose is highly expressed in the developing nervous system but nothing is known about it s function. We show that Rugose is present at the opposite side of the&n bsp;cis-Golgi marker GM130 and colocalizes with transgenic Nbea. W e also demonstrated that Nbea is the functional homolog of Rugose at the level of eye development, NMJ architecture and associative odor learnin g. Expression of Rugose in the mushroom bodies, which are important for learning and memory, is necessary and sufficient to rescue the phenotype . Moreover, Rugose function in associative odor learning is required dur ing development since acute expression in the adult alone fails to resto re the associative odor learning defect. This developmental origin of th e associative learning defect is in agreement with the developmental nat ure of ASD. In order to further elucidate Rugose function, an u nbiased genomic screen was performed by means of deficiencies, based on the rough eye phenotype of rugose mutants. In a first screen, genes implicated in the Notch and EGFR pathway, like EGFR,&n bsp;Sprouty and Star, and genes implicated in vesicle t ransport, like sec15, Rab11, Klc, My o28B1, CG5522, Rab7, fab1, u nc-104 and synapsin, were identified as possible interacto rs of rugose. For unc-104, fab1 and possibly also Sprouty this interaction was also confirmed at the leve l of NMJ architecture. Some candidate genes for ASD are known to act in the same pathway like NLGNs, NRXNs and SHA NK3 supporting the idea that genes identified in this screen may be c andidate genes for ASD. From the identified interactors, especially synapsin has previously been linked to ASD. However, at whic h level precisely Rugose interacts with these modifiers, remains to be i nvestigated.