HGNC Approved Gene Symbol: PACS1
SNOMEDCT: 773581009;
Cytogenetic location: 11q13.1-q13.2 Genomic coordinates (GRCh38) : 11:66,070,272-66,244,744 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q13.1-q13.2 | Schuurs-Hoeijmakers syndrome | 615009 | Autosomal dominant | 3 |
PACS1 is a trans-Golgi-membrane traffic regulator that directs protein cargo and several viral envelope proteins. It is upregulated during human embryonic brain development and has low expression after birth (summary by Schuurs-Hoeijmakers et al., 2012).
By yeast 2-hybrid screening of a mouse embryo cDNA library to identify cytosolic proteins that bind directly to the phosphorylated furin (136950) cytosolic domain, Wan et al. (1998) identified cDNAs encoding Pacs1. Screening of a rat brain cDNA library with the Pacs1 sequences yielded 2 cDNAs representing splice variants. The larger variant, Pacs1a, has 961 amino acids, and the smaller variant, Pacs1b, has 559 amino acids. Both proteins contain the 140-amino acid furin-binding region (val115 to pro255). Northern blot analysis using transcript-specific probes showed that both Pacs1 variants were expressed ubiquitously, with the 4.4-kb Pacs1a transcript expressed more than 20-fold higher than the 3.6-kb Pacs1b transcript. Wan et al. (1998) also identified human ESTs containing PACS1 sequences.
Wan et al. (1998) reported that Pacs1 directs the trans-Golgi network (TGN) localization of furin by binding to its phosphorylated cytosolic domain. Antisense studies showed that TGN localization of furin and mannose 6-phosphate receptor (M6PR; 154540), but not TGN46 (603062), is strictly dependent on Pacs1. Analyses in vitro and in vivo showed that Pacs1 has properties of a coat protein and connects furin to components of the clathrin-sorting machinery. Cell-free assays indicated TGN localization of furin is directed by a Pacs1-mediated retrieval step. Together, these findings explained a mechanism by which membrane proteins in mammalian cells are localized to the TGN.
Blagoveshchenskaya et al. (2002) showed that the human immunodeficiency virus (HIV)-1 multifunctional early gene product Nef and cellular PACS1 combine to usurp the ARF6 (600464) endocytic pathway by a phosphatidylinositol 3-kinase (PI3K; see 171833)-dependent process and downregulate cell surface major histocompatibility complex (MHC) class I molecules to the TGN. They found that this mechanism requires the hierarchical actions of 3 Nef motifs, the acidic cluster glu62-glu63-glu64-glu65, the SH3 domain-binding site pro72-X-X-pro75, and met20, in controlling PACS1-dependent sorting to the TGN, ARF6 activation, and sequestering internalized MHC class I molecules to the TGN, respectively.
Polycystin-2 (PKD2; 173910) functions as a calcium-permeable nonselective cation channel at the plasma membrane or ER. Kottgen et al. (2005) found that the subcellular localization and function of polycystin-2 were directed by PACS1 and PACS2 (610423), which recognized an acidic cluster in the C-terminal domain of polycystin-2. Binding to these adaptor proteins was regulated by the phosphorylation of polycystin-2 on ser812 by casein kinase-2 (see CSNK2A1; 115440), required for the routing of polycystin-2 between ER, Golgi, and the plasma membrane compartments. Kottgen et al. (2005) concluded that PACS1 and PACS2 are involved in ion channel trafficking, directing acid cluster-containing ion channels to distinct subcellular compartments.
By radiation hybrid and genomic database analysis, Simmen et al. (2005) mapped the PACS1 gene to chromosome 11q13.1.
In 2 unrelated boys with mental retardation and a strikingly similar facial appearance (SHMS; 615009), Schuurs-Hoeijmakers et al. (2012) identified a recurrent de novo mutation in the PACS1 gene, resulting in a missense mutation (R203W; 607492.0001) in the furin (cargo) binding region directly adjacent to the CK2 binding motif. Schuurs-Hoeijmakers et al. (2012) found that altered PACS1 forms cytoplasmic aggregates in vitro with concomitant increased stability and showed impaired binding to an isoform-specific variant of TRPV4 (605427), but not the full-length protein. Furthermore, consistent with the human pathology, expression of mutant PACS1 mRNA in zebrafish embryos induced craniofacial defects most likely in a dominant-negative fashion. The phenotype was driven by aberrant specification and migration of SOX10 (602229)-positive cranial, but not enteric, neural crest cells.
In a 3-year-old boy with SHMS, Gadzicki et al. (2015) identified the same de novo heterozygous c.607C-T transition in exon 4 of the PACS1 gene. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing.
Schuurs-Hoeijmakers et al. (2016) reported 16 additional patients with SHMS resulting from the recurrent de novo heterozygous R203W mutation in the PACS1 gene. All of the patients were diagnosed by exome sequencing.
Martinez-Monseny et al. (2018) identified de novo heterozygosity for the R203W mutation in the PACS1 gene in a 12-year-old girl with SHMS. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing.
By whole-exome sequencing in 2 Japanese children with SHMS, Hoshino et al. (2019) identified the recurrent de novo heterozygous R203W mutation in the PACS1 gene.
In 2 unrelated boys with mental retardation and a strikingly similar facial appearance (SHMS; 615009), Schuurs-Hoeijmakers et al. (2012) identified the same de novo heterozygous mutation in the PACS1 gene: a 607C-T transition resulting in an arg203-to-trp (R203W) substitution. The mutation was not identified in 150 alleles from the Dutch population, in 2,304 alleles from the local variant database, or in 7,020 alleles of European American origin from the NHLBI Exome Sequencing Project database.
In a 3-year-old boy with SHMS, Gadzicki et al. (2015) identified the same de novo heterozygous c.607C-T transition in exon 4 of the PACS1 gene. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing.
Schuurs-Hoeijmakers et al. (2016) reported 16 additional patients with SHMS resulting from the recurrent de novo heterozygous R203W mutation in the PACS1 gene. All of the patients were diagnosed by exome sequencing.
Martinez-Monseny et al. (2018) identified de novo heterozygosity for the R203W mutation in the PACS1 gene in a 12-year-old girl with SHMS. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing.
By whole-exome sequencing in 2 Japanese children with SHMS, Hoshino et al. (2019) identified the recurrent de novo heterozygous R203W mutation in the PACS1 gene.
Blagoveshchenskaya, A. D., Thomas, L., Feliciangeli, S. F., Hung, C.-H., Thomas, G. HIV-1 Nef downregulates MHC-I by a PACS-1- and PI3K-regulated ARF6 endocytic pathway. Cell 111: 853-866, 2002. [PubMed: 12526811] [Full Text: https://doi.org/10.1016/s0092-8674(02)01162-5]
Gadzicki, D., Docker, D., Schubach, M., Menzel, M., Schmorl, B., Stellmer, F., Biskup, S., Bartholdi, D. Expanding the phenotype of a recurrent de novo variant in PACS1 causing intellectual disability. (Letter) Clin. Genet. 88: 300-302, 2015. [PubMed: 25522177] [Full Text: https://doi.org/10.1111/cge.12544]
Hoshino, Y., Enokizono, T., Imagawa, K., Tanaka, R., Suzuki, H., Fukushima, H., Arai, J., Sumazaki, R., Uehara, T., Takenouchi, T., Kosaki, K. Schuurs-Hoeijmakers syndrome in two patients from Japan. Am. J. Med. Genet. 179A: 341-343, 2019. [PubMed: 30588754] [Full Text: https://doi.org/10.1002/ajmg.a.9]
Kottgen, M., Benzing, T., Simmen, T., Tauber, R., Buchholz, B., Feliciangeli, S., Huber, T. B., Schermer, B., Kramer-Zucker, A., Hopker, K., Simmen, K. C., Tschucke, C. C., Sandford, R., Kim, E., Thomas, G., Walz, G. Trafficking of TRPP2 by PACS proteins represents a novel mechanism of ion channel regulation. EMBO J. 24: 705-716, 2005. [PubMed: 15692563] [Full Text: https://doi.org/10.1038/sj.emboj.7600566]
Martinez-Monseny, A., Bolasell, M., Arjona, C., Martorell, L., Yubero, D., Armstrong, J., Maynou, J., Fernandez, G., del Carmen Salgado, M., Palau, F., Serrano, M. Mutation of PACS1: the milder end of the spectrum. Clin. Dysmorph. 27: 148-150, 2018. [PubMed: 30113927] [Full Text: https://doi.org/10.1097/MCD.0000000000000237]
Schuurs-Hoeijmakers, J. H. M., Landsverk, M. L., Foulds, N., Kukolich, M. K., Gavrilova, R. H., Greville-Heygate, S., Hanson-Kahn, A., Bernstein, J. A., Glass, J., Chitayat, D., Burrow, T. A., Husami, A., and 27 others. Clinical delineation of the PACS1-related syndrome--report on 19 patients. Am. J. Med. Genet. 170A: 670-675, 2016. [PubMed: 26842493] [Full Text: https://doi.org/10.1002/ajmg.a.37476]
Schuurs-Hoeijmakers, J. H. M., Oh, E. C., Vissers, L. E. L. M., Swinkels, M. E. M., Gilissen, C., Willemsen, M. A., Holvoet, M., Steehouwer, M., Veltman, J. A., de Vries, B. B. A., van Bokhoven, H., de Brouwer, A. P. M., Katsanis, N., Devriendt, K., Brunner, H. G. Recurrent de novo mutations in PACS1 cause defective cranial neural-crest migration and define a recognizable intellectual-disability syndrome. Am. J. Hum. Genet. 91: 1122-1127, 2012. [PubMed: 23159249] [Full Text: https://doi.org/10.1016/j.ajhg.2012.10.013]
Simmen, T., Aslan, J. E., Blagoveshchenskaya, A. D., Thomas, L., Wan, L., Xiang, Y., Feliciangeli, S. F., Hung, C.-H., Crump, C. M., Thomas, G. PACS-2 controls endoplasmic reticulum-mitochondria communication and Bid-mediated apoptosis. EMBO J. 24: 717-729, 2005. Note: Erratum: EMBO J. 24: 1301 only, 2005. [PubMed: 15692567] [Full Text: https://doi.org/10.1038/sj.emboj.7600559]
Wan, L., Molloy, S. S., Thomas, L., Liu, G., Xiang, Y., Rybak, S. L., Thomas, G. PACS-1 defines a novel gene family of cytosolic sorting proteins required for trans-Golgi network localization. Cell 94: 205-216, 1998. [PubMed: 9695949] [Full Text: https://doi.org/10.1016/s0092-8674(00)81420-8]