Alternative titles; symbols
HGNC Approved Gene Symbol: AP1S1
SNOMEDCT: 722035007;
Cytogenetic location: 7q22.1 Genomic coordinates (GRCh38) : 7:101,154,476-101,161,276 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q22.1 | MEDNIK syndrome | 609313 | Autosomal recessive | 3 |
The AP1S1 gene encodes the small subunit of the AP-1 complex, which is involved in protein trafficking by clathrin-coated vesicles. Clathrin and its associated heterotetrameric protein complexes (APs) are the main protein components of the coat surrounding the cytoplasmic face of coated vesicles. Two main types of APs, AP-1 and AP-2, are found in clathrin-coated structures located at the Golgi complex and the plasma membrane of mammalian cells, respectively. AP-1 is composed of 2 large chains, beta-prime-adaptin (600157) and gamma-adaptin (603533); a medium (mu) chain, AP47 (603535); and a small (sigma) chain, AP19 (summary by Kirchhausen et al., 1991).
Kirchhausen et al. (1991) isolated cDNAs encoding mouse AP19 and rat AP17 (602242), the small subunit of AP-2. The predicted rat AP17 shares 45% protein sequence identity with mouse AP19. Takatsu et al. (1998) identified a human cDNA encoding AP19, which they designated sigma-1A. They reported that the predicted mouse and human AP19 proteins are identical. Northern blot analysis revealed that the approximately 1.4-kb AP19 mRNA was expressed ubiquitously in human tissues.
Doray et al. (2002) demonstrated that the Golgi-localized, gamma-ear-containing adenosine diphosphate ribosylation factor-binding proteins (GGA1, 606004 and GGA3, 606006) and the AP-1 complex colocalize in clathrin-coated buds of the trans-Golgi networks of mouse L cells and human HeLa cells. Binding studies revealed a direct interaction between the hinge domains of the GGAs and the gamma-ear domain of AP-1. Further, AP-1 contained bound casein kinase-2 (see CSNK2A1, 115440) that phosphorylated GGA1 and GGA3, thereby causing autoinhibition. Doray et al. (2002) demonstrated that this autoinhibition could induce the directed transfer of mannose 6-phosphate receptors (see 154540) from the GGAs to AP-1. Mannose 6-phosphate receptors that were defective in binding to GGAs were poorly incorporated into adaptor protein complex containing clathrin coated vesicles. Thus, Doray et al. (2002) concluded that GGAs and the AP-1 complex interact to package mannose 6-phosphate receptors into AP-1-containing coated vesicles.
Using a library of endoribonuclease-prepared short interfering RNAs (esiRNAs), Kittler et al. (2004) identified 37 genes required for cell division, one of which was AP1S1. These 37 genes included several splicing factors for which knockdown generates mitotic spindle defects. In addition, a putative nuclear-export terminator was found to speed up cell proliferation and mitotic progression after knockdown.
By analysis of a somatic cell hybrid panel, Peyrard et al. (1998) mapped the AP19 gene to human chromosome 7.
In affected members of 4 families from Quebec with MEDNIK syndrome (MEDNIK; 609313), Montpetit et al. (2008) identified a homozygous splice site mutation in the AP1S1 gene (603531.0001). The mutation was identified by linkage analysis followed by candidate gene sequencing. The mutation was predicted to result in a truncated protein with loss of function, but a small amount of an AP1S1 protein with an in-frame deletion was also produced, which may have contributed some residual activity. Knockdown of the Ap1s1 gene in zebrafish resulted in skin and neurologic defects (see ANIMAL MODEL).
In an 8-year-old girl, born of consanguineous Sephardic Jewish parents, with MEDNIK, Martinelli et al. (2013) identified homozygosity for a 1-bp insertion of a G within a string of Gs (nucleotides 356-365) in exon 4 of the AP1S1 gene (603531.0002). In a 10-year-old girl, born to consanguineous Turkish parents, with MEDNIK, Incecik et al. (2018) identified the mutation as a duplication at nucleotide 364 (c.364dupG). Martinelli et al. (2013) found the mutation by whole-exome sequencing and Incecik et al. (2018) found it by targeted gene sequencing. The mutation segregated with the disorder in both families. Martinelli et al. (2013) found that fibroblasts in their patient showed an 80-fold reduction of AP1S1 mRNA expression and absence of AP1S1 protein expression.
Montpetit et al. (2008) found that knockdown of the Ap1s1 gene in zebrafish caused smaller larvae with reduced pigmentation compared to wildtype. The larvae had prominent changes in the skin organization with disorganized fins. Immunolabeling showed abnormal localization of laminin (see, e.g., 150320) and cadherin (see, e.g., 192090) in the skin, which was predicted to lead to a loss of epidermal layer integrity. Knockdown of Ap1s1 in zebrafish also caused severe motor impairment and impaired spinal cord development with decreased numbers of interneurons. These defects could be rescued by injection of human wildtype AP1S1. Knockdown of Ap1s1 was lethal at later embryonic stages.
In affected members of 4 families from Quebec with impaired intellectual development, enteropathy, deafness, neuropathy, ichthyosis, and keratoderma (MEDNIK; 609313), Montpetit et al. (2008) identified a homozygous A-to-G transition in intron 2 of the AP1S1 gene, resulting in the skipping of exon 3 and premature termination, consistent with a loss of function. RT-PCR analysis of patient fibroblasts showed no full-length AP1S1 mRNA species, but there was an mRNA isoform predicted to result in a protein with an in-frame deletion generated by use of a cryptic splice acceptor site. Patients had less than 10% of the expected amount of mRNA, but the in-frame deletion protein may have contributed some residual activity. The mutation was found by linkage analysis followed by candidate gene sequencing. All unaffected parents were heterozygous for the mutation, which was not found in 180 controls.
In fibroblasts from a French Canadian patient (patient 4) with the homozygous IVS2-2A-G transition in the AP1S1 gene, Martinelli et al. (2013) showed mislocalization of the ATP7A (300011) protein to the cell periphery both at baseline and after increased copper supplementation, whereas in control cells the ATP7A protein was localized to the trans-Golgi network at baseline. Overexpression of wildtype AP1S1 in patient fibroblasts restored the correct localization of ATP7A to the trans-Golgi network. Martinelli et al. (2013) also showed decreased expression of the copper-containing enzymes superoxide dismutase (147450), COX II, and COX IV, and a severe reduction of COX activity in patient fibroblasts.
In an 8-year-old girl (patient 1), born to consanguineous Sephardic Jewish parents, with impaired intellectual development, enteropathy, deafness, neuropathy, ichthyosis, and keratoderma (MEDNIK; 609313), Martinelli et al. (2013) identified a homozygous 1-bp insertion (c.356_365insG) in a stretch of 8 consecutive Gs between nucleotides 356 and 365 in exon 4 of the AP1S1 gene, predicting a frameshift and stop codon after 17 amino acids (Asp322GlyfsTer17). The mutation, which was identified by targeted gene sequencing, was present in heterozygous state in the parents and an unaffected sib. Patient fibroblasts showed an 80-fold reduction of AP1S1 mRNA expression and absence of AP1S1 protein expression. The carrier parents and sister showed a 40-fold reduction in APS1 mRNA expression. Patient fibroblasts showed decreased expression of the copper-containing enzymes superoxide dismutase (147450), COX II, and COX IV, and a severe reduction of COX activity. There was also mislocalization of the ATP7A protein (300011) to the cell periphery both at baseline and after increased copper supplementation n patient fibroblasts, whereas in control cells the ATP7A protein was localized to the trans-Golgi network at baseline. Overexpression of wildtype AP1S1 in patient fibroblasts restored the correct localization of ATP7A, and incorporation rate and copper retention rate were both reduced in patient fibroblasts compared to controls.
In a 10-year-old girl with MEDNIK, born to consanguineous Turkish parents, Incecik et al. (2018) identified homozygosity for this 1-bp duplication of a G at nucleotide 364 (c.364dupG, NM_001283.4) in the AP1S1 gene, predicting a frameshift and a premature termination codon 18 residues downstream (Glu122GlyfsTer18). The mutation was identified by targeted gene sequencing. The parents were heterozygous for the mutation. Functional studies were not performed.
Doray, B., Ghosh, P., Griffith, J., Geuze, H. J., Kornfeld, S. Cooperation of GGAs and AP-1 in packaging MPRs at the trans-Golgi network. Science 297: 1700-1703, 2002. [PubMed: 12215646] [Full Text: https://doi.org/10.1126/science.1075327]
Incecik, F., Bisgin, A., Yilmaz, M. MEDNIK syndrome with a frame shift causing mutation in AP1S1 gene and literature review of the clinical features. Metab. Brain Dis. 33: 2065-2068, 2018. [PubMed: 30244301] [Full Text: https://doi.org/10.1007/s11011-018-0313-4]
Kirchhausen, T., Davis, A. C., Frucht, S., O'Brine Greco, B., Payne, G. S., Tubb, B. AP17 and AP19, the mammalian small chains of the clathrin-associated protein complexes show homology to Yap17p, their putative homolog in yeast. J. Biol. Chem. 266: 11153-11157, 1991. [PubMed: 2040623]
Kittler, R., Putz, G., Pelletier, L., Poser, I., Heninger, A.-K., Drechsel, D., Fischer, S., Konstantinova, I., Habermann, B., Grabner, H., Yaspo, M.-L., Himmelbauer, H., Korn, B., Neugebauer, K., Pisabarro, M. T., Buchholz, F. An endoribonuclease-prepared siRNA screen in human cells identifies genes essential for cell division. Nature 432: 1036-1040, 2004. [PubMed: 15616564] [Full Text: https://doi.org/10.1038/nature03159]
Martinelli, D., Travaglini, L., Drouin, C. A., Ceballos-Picot, I., Rizza, T., Bertini, E., Carrozzo, R., Petrini, S., de Lonlay, P., El Hachem, M., Hubert, L., Montpetit, A., Torre, G., Dionisi-Vici, C. MEDNIK syndrome: a novel defect of copper metabolism treatable by zinc acetate therapy. Brain 136: 872-881, 2013. Note: Erratum: Brain 136: e256, 2013. [PubMed: 23423674] [Full Text: https://doi.org/10.1093/brain/awt012]
Montpetit, A., Cote, S., Brustein, E., Drouin, C. A., Lapointe, L., Boudreau, M., Meloche, C., Drouin, R., Hudson, T. J., Drapeau, P., Cossette, P. Disruption of AP1S1, causing a novel neurocutaneous syndrome, perturbs development of the skin and spinal cord. PLoS Genet. 4: e1000296, 2008. Note: Electronic Article. [PubMed: 19057675] [Full Text: https://doi.org/10.1371/journal.pgen.1000296]
Peyrard, M., Parveneh, S., Lagercrantz, S., Ekman, M., Fransson, I., Sahlen, S., Dumanski, J. P. Cloning, expression pattern, and chromosomal assignment to 16q23 of the human gamma-adaptin gene (ADTG). Genomics 50: 275-280, 1998. [PubMed: 9653655] [Full Text: https://doi.org/10.1006/geno.1998.5289]
Takatsu, H., Sakurai, M., Shin, H.-W., Murakami, K., Nakayama, K. Identification and characterization of novel clathrin adaptor-related proteins. J. Biol. Chem. 273: 24693-24700, 1998. [PubMed: 9733768] [Full Text: https://doi.org/10.1074/jbc.273.38.24693]