Abstract
Autism spectrum disorders (ASDs) are a group of commonly occurring, highly-heritable developmental disabilities. Human genes c3orf58 or Deleted In Autism-1 (DIA1) and cXorf36 or Deleted in Autism-1 Related (DIA1R) are implicated in ASD and mental retardation. Both gene products encode signal peptides for targeting to the secretory pathway. As evolutionary medicine has emerged as a key tool for understanding increasing numbers of human diseases, we have used an evolutionary approach to study DIA1 and DIA1R. We found DIA1 conserved from cnidarians to humans, indicating DIA1 evolution coincided with the development of the first primitive synapses. Nematodes lack a DIA1 homologue, indicating Caenorhabditis elegans is not suitable for studying all aspects of ASD etiology, while zebrafish encode two DIA1 paralogues. By contrast to DIA1, DIA1R was found exclusively in vertebrates, with an origin coinciding with the whole-genome duplication events occurring early in the vertebrate lineage, and the evolution of the more complex vertebrate nervous system. Strikingly, DIA1R was present in schooling fish but absent in fish that have adopted a more solitary lifestyle. An additional DIA1-related gene we named DIA1-Like (DIA1L), lacks a signal peptide and is restricted to the genomes of the echinoderm Strongylocentrotus purpuratus and cephalochordate Branchiostoma floridae. Evidence for remarkable DIA1L gene expansion was found in B. floridae. Amino acid alignments of DIA1 family gene products revealed a potential Golgi-retention motif and a number of conserved motifs with unknown function. Furthermore, a glycine and three cysteine residues were absolutely conserved in all DIA1-family proteins, indicating a critical role in protein structure and/or function. We have therefore identified a new metazoan protein family, the DIA1-family, and understanding the biological roles of DIA1-family members will have implications for our understanding of autism and mental retardation.
Highlights
Autism spectrum disorder (ASD) is a neurodevelopmental condition commonly diagnosed in early childhood
Reciprocal pair-wise E-values between C. intestinalis Deleted In Autism-1 (DIA1), and DIA1 and Deleted in Autism-1 Related (DIA1R) of the same key vertebrate species (H. sapiens, M. musculus, G. gallus, D. rerio), were generated (Table S7). These analyses revealed that C. intestinalis DIA1 showed greater similarity to DIA1, than DIA1R orthologues using the Basic Local Alignment Search Tool (BLAST) algorithm (Table S7), with E-values of around e-32 when compared to the vertebrate DIA1 proteins, Figure 4
As we propose the DIA1 and DIA1R gene products play a ubiquitous role in the secretory pathway [39], it is possible that DIA1-family homologues play a role in generating these ostariophysan-specific features
Summary
Autism spectrum disorder (ASD) is a neurodevelopmental condition commonly diagnosed in early childhood. Many of the genes implicated in ASD have direct or indirect roles in synapse formation and function [13,14,15,16,17,18,19]. The secretory pathway plays a key role in neuron function, and abnormalities in secretion and secretory cargo have been found in increasing numbers of ASD patients [20,21,22,23]. Genes affecting secretory pathway traffic are reported to be affected in those with ASD [12,24]. Post-translational modification of proteins in the secretory pathway via phosphorylation and sulphation are abnormal in ASD patients, as are genes involved in glycosylation events within the Golgi apparatus lumen [12,25,26,27,28]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
