Submission Details

AP1S1 was first reported in relation to autosomal recessive MEDNIK syndrome (MIM:609313) in 2008 (Montpetit et al., PMID:19057675). MEDNIK syndrome is a very rare congenital disorder characterized by mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma (PMID: 24754424). Another common feature is copper metabolism defects, leading to reduced ceruloplasmin in the serum and liver copper overload (PMID: 31399000). These underlying defects in copper metabolism are consistent with the known role of AP1S1 in mediating the intracellular trafficking of copper transporters ATP7A and ATP7B (PMID: 31399000).

Two variants (one canonical splice site and one frameshift) that have been reported in six probands in four publications (PMID: 19057675, 23423674, 30244301, 32306098) are included in this curation. Minimal segregation evidence was available in these publications, and did not contribute to the scoring of the gene-disease relationship.

The mechanism of pathogenicity appears to be biallelic loss of function, as all reported probands are homozygous for predicted/proven null alleles. AP1S1 encodes the sigma 1A subunit of the AP-1 complex, which participates in intracellular trafficking by promoting the formation of clathrin coated vesicles (PMID:31399000). The sigma 1A subunit plays a role in cargo recognition, lipid recognition, and maintaining AP-1 complex stability. Therefore, loss of AP-1 leads to missorting of intracellular cargoes, particularly in polarized cells such as neurons and epithelial cells, where AP-1 specifically traffics proteins from the trans-Golgi network to basolateral domains of the plasma membrane.

This gene-disease association is also supported by in vitro functional assays in both patient cells and a cell culture model, as well as a zebrafish model (PMID: 19057675, 23423674, 32306098). The ATP-dependent copper transporter ATP7A was found to be mislocalized in fibroblast cells from MEDNIK syndrome patients; in addition, the expression and function of cuproenzymes was disrupted in these cells. Transfection with a wild-type AP1S1 expression construct rescued these defects, demonstrating the specific role of AP1S1 (PMID:23433674). In an enterocyte cell culture model, loss of AP1S1 function led to the missorting of tight-junction proteins, resulting in defective epithelial barrier formation (PMID: 32306098). Similar observations were made in the epidermis of zebrafish following treatment with an AP1S1-targeted morpholino (PMID:19057675). These animals also had a movement disorder due to interneuron loss, consistent with the phenotypes observed in MEDNIK syndrome patients.

In summary, AP1S1 is definitively associated with autosomal recessive MEDNIK syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time without the emergence of contradictory evidence. This classification was approved by the ClinGen General Inborn Errors of Metabolism Gene Curation Expert Panel on June 10th, 2022 (SOP Version 8).