Erythrokeratodermia variabilis (EKV) is an autosomal dominant disease that causes skin lesions and thickening. In 2005, a novel mutation was identified in a small group of families with an atypical form of EKV. In addition to erythematous lesions and hyper-keratosis, affected individuals from these families have severe psychomotor retardation, peripheral neuropathy, sensorineural hearing loss and severe diarrhea. In a new study, a team of Canadian researchers report that the atypical form of EKV caused by this mutation is in fact a novel neurocu-taneous syndrome, which they have named MEDNIK (mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis and keratodermia). The mutation found in MEDNIK patients creates a premature stop codon in the AP1S1 gene, which encodes a subunit of an adaptor protein complex involved in protein trafficking within cells. The researchers show that knocking down Ap1s1 expression in zebrafish resulted in a phenotype reminiscent of the human syndromes, featuring aberrant skin formation and severe motor deficits owing to impaired neurodevelopment. Furthermore, injection of wild-type human AP1S1 mRNA rescued this phenotype, but injection of AP1S1 mRNA containing the MEDNICK mutation did not. These results confirm the role of this adapter protein subunit in the pathology of this newly reported disease.
Montpetit A, Côté S, Brustein E, Drouin CA, Lapointe L, Boudreau M, Meloche C, Drouin R, Hudson TJ, Drapeau P, et al. (2008). Disruption of AP1S1, causing a novel neurocutaneous syndrome, perturbs development of the skin and spinal cord. PLoS Genet. 4, e1000296.
