RGD Reference Report - Disruption of AP1S1, causing a novel neurocutaneous syndrome, perturbs development of the skin and spinal cord. - Rat Genome Database

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Disruption of AP1S1, causing a novel neurocutaneous syndrome, perturbs development of the skin and spinal cord.

Authors: Montpetit, A  Cote, S  Brustein, E  Drouin, CA  Lapointe, L  Boudreau, M  Meloche, C  Drouin, R  Hudson, TJ  Drapeau, P  Cossette, P 
Citation: Montpetit A, etal., PLoS Genet. 2008 Dec;4(12):e1000296. doi: 10.1371/journal.pgen.1000296. Epub 2008 Dec 5.
RGD ID: 9684947
Pubmed: PMID:19057675   (View Abstract at PubMed)
PMCID: PMC2585812   (View Article at PubMed Central)
DOI: DOI:10.1371/journal.pgen.1000296   (Journal Full-text)

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 sigma1A 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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
MEDNIK syndrome  IAGP 9684947DNA:mutation:splice junction:RGD 
MEDNIK syndrome  ISOAP1S1 (Homo sapiens)9684947; 9684947DNA:mutation:splice junction:RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ap1s1  (adaptor related protein complex 1 subunit sigma 1)

Genes (Mus musculus)
Ap1s1  (adaptor protein complex AP-1, sigma 1)

Genes (Homo sapiens)
AP1S1  (adaptor related protein complex 1 subunit sigma 1)


Additional Information