HGNC Approved Gene Symbol: AP4S1
Cytogenetic location: 14q12 Genomic coordinates (GRCh38) : 14:31,025,106-31,096,450 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q12 | Spastic paraplegia 52, autosomal recessive | 614067 | Autosomal recessive | 3 |
The heterotetrameric adaptor protein (AP) complexes sort integral membrane proteins at various stages of the endocytic and secretory pathways. AP4 is composed of 2 large chains, beta-4 (AP4B1; 607245) and epsilon-4 (AP4E1; 607244), a medium chain, mu-4 (AP4M1; 602296), and a small chain, sigma-4 (AP4S1) (summary by Hirst et al., 1999).
Dell'Angelica et al. (1999) cloned mouse Ap4s1. The predicted 144-amino acid Ap4s1 protein has a calculated molecular mass of 16.8 kD. Northern blot analysis revealed a 1.2- to 1.4-kb transcript in all mouse tissues examined. By gel filtration and Western blot analysis of human fibroblast cytosol, Dell'Angelica et al. (1999) found that AP4S1 shows an apparent molecular mass of about 17 kD and is part of a 280-kD complex containing AP4B1, AP4E1, and AP4M1. Immunolocalization of the AP4B1 subunit in HeLa cells indicated that the AP4 complex associates with the trans-Golgi network or an adjacent structure. The association was sensitive to brefeldin-A treatment, indicating that the membrane localization of AP4 is dependent upon the small GTP-binding protein ARF1 (103180).
Hirst et al. (1999) identified AP4S1 within an EST from human placenta. The deduced AP4S1 protein contains 144 amino acids and shares 30 to 40% sequence identity with AP1S (see 603531), AP2S (602242), and AP3S (see 601507). Using a yeast 2-hybrid analysis, Hirst et al. (1999) found strong and specific interaction between AP4E1 and AP4S1.
Abou Jamra et al. (2011) found ubiquitous AP4S1 expression in all fetal and adult brain structures examined.
The International Radiation Hybrid Mapping Consortium mapped the AP4S1 gene to chromosome 14 (H00269).
By linkage analysis followed by exome sequencing of a consanguineous Syrian family with autosomal recessive mental retardation and spasticity (SPG52; 614067), Abou Jamra et al. (2011) identified a homozygous truncating mutation in the AP4S1 gene (R42X; 607243.0001).
In 2 sisters, born of unrelated Caucasian parents, with SPG52 and seizures, Hardies et al. (2015) identified compound heterozygous truncating mutations in the AP4S1 gene (607243.0002 and 607243.0003). The mutations, which were found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Western blot analysis of cells derived from 1 sister showed absence of the AP4S1 protein and a substantial reduction in all other AP4 subunits compared to controls. Immunoprecipitation studies confirmed the reduction of AP4 subunits and also showed impaired assembly of the complex. The findings implicated a defect in endosomal trafficking in both epilepsy and spastic paraplegia.
By linkage analysis followed by exome sequencing of a consanguineous Syrian family with autosomal recessive mental retardation and spasticity (SPG52; 614067), Abou Jamra et al. (2011) identified a homozygous 124C-T transition in exon 2 of the AP4S1 gene, resulting in an arg42-to-ter (R42X) substitution. The mutation was not found in 740 control chromosomes of Syrian descent.
In 2 sisters, born of unrelated Caucasian parents, with autosomal recessive spastic paraplegia-52 (SPG52; 614067), Hardies et al. (2015) identified compound heterozygous mutations in the AP4S1 gene: a 4-bp deletion (c.137_140delAAGT, NM_007077.4), resulting in a frameshift and premature termination (Gln46ProfsTer9), and a c.289C-T transition, resulting in an arg97-to-ter (R97X; 607243.0003) substitution. The mutations, which were found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutations were filtered against the 1000 Genomes Project and Exome Variant Server databases and 30 in-house genomes. The R97X variant was found at a low frequency (0.015%) in the Exome Variant Server. Western blot analysis of cells derived from 1 sister showed absence of the AP4S1 protein and a substantial reduction in all other AP4 subunits compared to controls. Immunoprecipitation studies confirmed the reduction of AP4 subunits and also showed impaired assembly of the complex.
For discussion of the c.289C-T transition (c.289C-T, NM_007077.4) in the AP4S1 gene resulting in an arg97-to-ter (R97X) substitution that was found in compound heterozygous state in patients with autosomal recessive spastic paraplegia-52 (SPG52; 614067) by Hardies et al. (2015), see 607243.0002.
Abou Jamra, R., Philippe, O., Raas-Rothschild, A., Eck, S. H., Graf, E., Buchert, R., Borck, G., Ekici, A., Brockschmidt, F. F., Nothen, M. M., Munnich, A., Strom, T. M., Reis, A., Colleaux, L. Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature. Am. J. Hum. Genet. 88: 788-795, 2011. [PubMed: 21620353] [Full Text: https://doi.org/10.1016/j.ajhg.2011.04.019]
Dell'Angelica, E. C., Mullins, C., Bonifacino, J. S. AP-4, a novel protein complex related to clathrin adaptors. J. Biol. Chem. 274: 7278-7285, 1999. [PubMed: 10066790] [Full Text: https://doi.org/10.1074/jbc.274.11.7278]
Hardies, K., May, P., Djemie, T., Tarta-Arsene, O., Deconinck, T., Craiu, D., AR Working Group of the EuroEPINOMICS RES Consortium, Helbig, I., Suls, A., Balling, R., Weckhuysen, S., De Jonghe, P., Hirst, J. Recessive loss-of-function mutations in AP4S1 cause mild fever-sensitive seizures, developmental delay and spastic paraplegia through loss of AP-4 complex assembly. Hum. Molec. Genet. 24: 2218-2227, 2015. [PubMed: 25552650] [Full Text: https://doi.org/10.1093/hmg/ddu740]
Hirst, J., Bright, N. A., Rous, B., Robinson, M. S. Characterization of a fourth adaptor-related protein complex. Molec. Biol. Cell 10: 2787-2802, 1999. [PubMed: 10436028] [Full Text: https://doi.org/10.1091/mbc.10.8.2787]