Characterization of the Deleted in Autism 1 Protein Family: Implications for Studying Cognitive Disorders

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.

Extracellular and Intracellular Signaling for Neuronal Polarity

“…DIA1 is localized to the Golgi complex and is primarily expressed in mesenchymal and cartilaginous tissues but is also mildly expressed in the cortical hem of the cerebral cortex (332). Although this gene has been implicated in autism spectrum disorder (ASD), its function remains unclear (15,226).…”

An Evolutionary Biology Approach to Understanding Neurological Disorders

“…While DIA1 is conserved from cnidaria to humans, it is not detected in nematodes, suggesting C. elegans is not a suitable model in which to study the cellular role of this gene. Strikingly, a related gene was found in humans using phylogenetic-based analyses, DIA1R, which localizes to the X chromosome (Aziz et al, 2011b). DIA1R is vertebrate-specific and, as with DIA1, is implicated in ASD (Aziz et al, 2011a(Aziz et al, , 2011b.…”

“…Strikingly, a related gene was found in humans using phylogenetic-based analyses, DIA1R, which localizes to the X chromosome (Aziz et al, 2011b). DIA1R is vertebrate-specific and, as with DIA1, is implicated in ASD (Aziz et al, 2011a(Aziz et al, , 2011b. Of possible relevance to the ASD phenotype, DIA1R had been 'lost' in fish of a solitary nature, while those retaining the gene are 'social' schooling fish (Aziz et al, 2011b).…”

“…DIA1R is vertebrate-specific and, as with DIA1, is implicated in ASD (Aziz et al, 2011a(Aziz et al, , 2011b. Of possible relevance to the ASD phenotype, DIA1R had been 'lost' in fish of a solitary nature, while those retaining the gene are 'social' schooling fish (Aziz et al, 2011b). Of further relevance to the use of animal models, DIA1R was found to be X-inactivated in mouse, but not in humans (Aziz et al, 2011b;Yang et al, 2010), and splicing may be species-specific.…”

“…Of possible relevance to the ASD phenotype, DIA1R had been 'lost' in fish of a solitary nature, while those retaining the gene are 'social' schooling fish (Aziz et al, 2011b). Of further relevance to the use of animal models, DIA1R was found to be X-inactivated in mouse, but not in humans (Aziz et al, 2011b;Yang et al, 2010), and splicing may be species-specific. Indeed, we have preliminary evidence for brain-specific splicing of DIA1 that is primate-specific, and not found in other vertebrate lineages (Aziz & Bishop, unpublished data).…”