Disruption of AP1S1, Causing a Novel Neurocutaneous Syndrome, Perturbs Development of the Skin and Spinal Cord

Abstract

Adaptor protein (AP) complexes regulate clathrin-coated vesicle assembly, protein cargo sorting, and vesicular trafficking between organelles in eukaryotic cells. Because disruption of the various subunits of the AP complexes is embryonic lethal in the majority of cases, characterization of their function in vivo is still lacking. Here, we describe the first mutation in the human AP1S1 gene, encoding the small subunit σ1A of the AP-1 complex. This founder splice mutation, which leads to a premature stop codon, was found in four families with a unique syndrome characterized by mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratodermia (MEDNIK). To validate the pathogenic effect of the mutation, we knocked down Ap1s1 expression in zebrafish using selective antisens morpholino oligonucleotides (AMO). The knockdown phenotype consisted of perturbation in skin formation, reduced pigmentation, and severe motility deficits due to impaired neural network development. Both neural and skin defects were rescued by co-injection of AMO with wild-type (WT) human AP1S1 mRNA, but not by co-injecting the truncated form of AP1S1, consistent with a loss-of-function effect of this mutation. Together, these results confirm AP1S1 as the gene responsible for MEDNIK syndrome and demonstrate a critical role of AP1S1 in development of the skin and spinal cord.

Author Summary

We describe a novel genetic syndrome that we named MEDNIK, to designate a disease characterized by mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis and keratodermia. This syndrome was found in four French-Canadian families with a common ancestor and is caused by a mutation in the AP1S1 gene. This gene encodes a subunit (σ1A) of an adaptor protein complex (AP-1) involved in the organisation and transport of many other proteins within the cell. By using rapidly developing zebrafish embryos as a model, we observed that the loss of this gene resulted in broad defects, including skin malformation and severe motor deficits due to impairment of spinal cord development. By expressing the human AP1S1 gene instead of the zebrafish ap1s1 gene, we found that the normal human AP1S1 gene could rescue these developmental deficits but not the human AP1S1 gene bearing the disease-related mutation. Together, our results confirm AP1S1 as the gene responsible for MEDNIK syndrome and demonstrate a critical role of AP1S1 in the development of the skin and the spinal cord.