ABSTRACT
Individuals with Down syndrome have neurological and muscle impairments due to an additional copy of the human 21st chromosome (HSA21). HSA21 is conservatively estimated to contain 213 genes that encode protein. Only a few of these genes have been linked to specific Down syndrome phenotypes, while the remainder are understudied. To gain insight into the in vivo roles of these genes, we studied loss-of-function phenotypes of all HSA21 orthologs in the nematode Caenorhabditis elegans. Excluding the expansion of keratin genes, 52% of HSA21 genes have a potential ortholog in C. elegans. Knock-down using RNA interference of 26% of HSA21 orthologs yielded phenotypes suggestive of neuronal and/or muscle dysfunction. Additionally, four genes were identified in an RNAi screen for decreased acetylcholine transmission. We conducted further study of synaptic transmission and neuromuscular function by quantitative analysis of several behaviors for defined HSA21 orthologs with loss-of-function mutants. Mutations in four genes caused defects in acetylcholine secretion. These include orthologs of NCAM2 (ncam-1), SYNJ1 (unc-26), PDXK (pdxk-1) as well as for a poorly characterized gene, N6AMT1 (mtq-2). As the first systematic functional analysis of HSA21 genes, this study may serve as a platform to understand genes that underlie phenotypes associated with Down syndrome.
ARTICLE SUMMARY Down syndrome causes neurological and muscle dysfunction due to an extra 21st chromosome. This chromosome has over 200 genes, most of which are understudied. To address this, we studied whether reducing function of these gene equivalents in the worm C. elegans caused neuronal or muscle defects. We found evidence that about one quarter of genes conserved between human and worm may function in neurons, muscle, or both. Among these, the highly conserved but uncharacterized neuronal gene, mtq-2, was found to be important for synaptic transmission. Our analysis may reveal novel functions of genes that cause problems in Down syndrome.
