AP1S2 gene is located on Xp22.2 human chromosome and encodes a 157-amino acid peptide, the sigma-2 subunit of the heterotetrameric adaptor protein 1 (AP1) complex.
AP1S2 consists of 5 exons, with the first nucleotide of exon 2 being the first coding sequence and the stop codon placed in the last exon. Most of the AP1S2 variants are nonsense and splice site mutations.
All identified AP1S2 variants were loss-of-function mutations. The splicing defects and leakage of splicing caused by the variant that affects the translational start site of AP1S2, specifically c.1-2A>G, have the potential to affect the severity of disease in patients. The activation of cryptic splice site (transcript band B) to produce potentially functional protein was found in male patients but not in carrier females. The finding is most likely caused by the need for genetic compensation to produce functional proteins that are essential for cellular maintenance.
The AP1S2 complex is found in the cytosolic side of coated vesicle in the Golgi compartment, it is generally responsible for clathrin-dependent endocytosis pathway (it controls the trafficking between the trans-Golgi network and plasma membrane, mediates the recruitment of clathrin and the recognition of sorting signals of transmembrane receptors).
So AP1S2 defects result in aberrant endocytic processing and membrane protein trafficking and have been considered part of the adaptinopathies, a group of disorders that includes several conditions, such as Hermansky–Pudlak syndrome type 2, MEDNIK syndrome –mental retardation, enteropathy, deafness, neuropathy, ichthyosis, keratodermia–and familial hypocalciuric hypercalcemia type 3, spastic paraplegia 47, 50, 51 and 52.
Folate deficiency is known to be associated with neural tube defects and hydrocephalus and AP1S2 mutations have been reported in patients with congenital hydrocephalus. The folate receptor is a glycosylphosphatidylinositol-anchored protein sorting from the trans-Golgi network to the plasma membrane. An AP1S2 defect, which involves endosomal trafficking, could negatively impact the processing and trafficking of folate receptor in patients with AP1S2 mutations, as folate receptors cycle to the cell surface via endosomal trafficking, ultimately resulting in the cerebral folate deficiency which can be found in these patients.
Nevertheless, evaluations of folate in CSF in other patients bringing AP1S2 mutations are needed to confirm this hypothesis.