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PACS1
Identifiers
Aliases	PACS1, MRD17, phosphofurin acidic cluster sorting protein 1, SHMS
External IDs	OMIM: 607492; MGI: 1277113; HomoloGene: 9970; GeneCards: PACS1; OMA:PACS1 - orthologs
Gene location (Human) Chr. Chromosome 11 (human) Band 11q13.1-q13.2 Start 66,070,272 bp End 66,244,744 bp
Gene location (Mouse) Chr. Chromosome 19 (mouse) Band 19|19 A Start 5,183,186 bp End 5,323,147 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in minor salivary glands granulocyte stromal cell of endometrium apex of heart cerebellar hemisphere right hemisphere of cerebellum right lung right coronary artery popliteal artery tibial arteries Top expressed in granulocyte seminiferous tubule internal carotid artery external carotid artery genital tubercle spermatid tail of embryo lacrimal gland zygote spermatocyte More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein binding transmembrane transporter binding Cellular component cytosol Golgi apparatus COPI-coated vesicle Biological process mitigation of host defenses by virus viral process protein localization to plasma membrane protein localization to Golgi apparatus Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 55690 107975 Ensembl ENSG00000175115 ENSMUSG00000024855 UniProt Q6VY07 Q8K212 RefSeq (mRNA) NM_018026 NM_178178 NM_153129 NM_001362451 RefSeq (protein) NP_060496 NP_060496.2 NP_694769 NP_001349380 NP_001390495 NP_001390496 NP_001390497 NP_001390498 Location (UCSC) Chr 11: 66.07 – 66.24 Mb Chr 19: 5.18 – 5.32 Mb PubMed search
Wikidata
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Phosphofurin acidic cluster sorting protein 1, also known as PACS-1, is a protein that in humans is encoded by the PACS1 gene.

Function

The PACS-1 protein has a putative role in the localization of trans-Golgi network (TGN) membrane proteins. Mouse and rat homologs have been identified and studies of the homologous rat protein indicate a role in directing TGN localization of furin by binding to the protease's phosphorylated cytosolic domain. In addition, the human protein plays a role in HIV-1 Nef-mediated downregulation of cell surface MHC-I molecules to the TGN, thereby enabling HIV-1 to escape immune surveillance.

Interactions

PACS1 has been shown to interact with Furin.

Clinical significance

A de novo mutation c.607C>T in the PACS1 gene has been shown to result in a syndromic phenotype (colloquially called PACS1 Syndrome) that is characterized by global developmental delay, intellectual disability, and specific facial features.

Prevalence and diagnosis

The first two cases were identified in early 2011 by doctors in the Netherlands. As of late 2014, there were 20 cases identified worldwide.

Diagnosis is typically done using full genome or exome sequencing. There are likely several more cases that will eventually be reported as knowledge of the mutation spreads and testing becomes more accessible.

Observed and reported traits

Individuals with the mutation have been reported to have similar facial features, such as:

• Widely spaced eyes and low-set ears
• Down-slanting eye corners and mild uni-brow
• Highly arched eyebrows and long eyelashes
• Rounded “button” nose with a flat bridge
• Wide mouth with down-turned corners
• Thin upper lip and widely spaced teeth

Other common traits reported by care givers of affected individuals are:

• Low muscle tone
• Seizures
• Repetitive self-stimulatory behavior
• Sensory processing disorder
• Delayed development of gross motor skills and fine motor skills
• Delayed cognitive development
• Chewing and swallowing difficulties
• Digestion or bowel problems
• Slow growth resulting in below average height and weight

Prognosis and treatment

In combination, these traits affect walking, talking, feeding, and learning skills. No impact on life expectancy has been found. As with many developmental disabilities, there is no "cure".

In order to improve quality of life and enhance life skills of affected individuals, care givers have found a number of tools and strategies. It is important to note that all of these may not be applicable to a particular individual, and reported effectiveness has varied. It is recommended to consult with a physician prior to initiating any form of treatment.

• physiotherapy (PT)
• occupational therapy (OT)
• speech therapy (including augmentative and alternative communication) (SPT)
• behavioural therapy (applied behavior analysis/intensive behavioural intervention etc.)
• discrete trial teaching
• early intervention programs
• massage therapy and pediatric massage
• feeding therapy
• music therapy
• hippotherapy
• hydrotherapy

References

1. ^ GRCh38: Ensembl release 89: ENSG00000175115 – Ensembl, May 2017
2. ^ GRCm38: Ensembl release 89: ENSMUSG00000024855 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Stove V, Naessens E, Stove C, Swigut T, Plum J, Verhasselt B (Oct 2003). "Signaling but not trafficking function of HIV-1 protein Nef is essential for Nef-induced defects in human intrathymic T-cell development". Blood. 102 (8): 2925–32. doi:10.1182/blood-2003-03-0833. PMID 12855553.
6. Hinners I, Wendler F, Fei H, Thomas L, Thomas G, Tooze SA (Dec 2003). "AP-1 recruitment to VAMP4 is modulated by phosphorylation-dependent binding of PACS-1". EMBO Reports. 4 (12): 1182–9. doi:10.1038/sj.embor.7400018. PMC 1326413. PMID 14608369.
7. ^ "Entrez Gene: PACS1 phosphofurin acidic cluster sorting protein 1".
8. ^ Wan L, Molloy SS, Thomas L, Liu G, Xiang Y, Rybak SL, Thomas G (Jul 1998). "PACS-1 defines a novel gene family of cytosolic sorting proteins required for trans-Golgi network localization". Cell. 94 (2): 205–16. doi:10.1016/S0092-8674(00)81420-8. PMID 9695949. S2CID 15027198.
9. ^ Schuurs-Hoeijmakers JH, Oh EC, Vissers LE, Swinkels ME, Gilissen C, Willemsen MA, Holvoet M, Steehouwer M, Veltman JA, de Vries BB, van Bokhoven H, de Brouwer AP, Katsanis N, Devriendt K, Brunner HG (2012). "Recurrent de novo mutations in PACS1 cause defective cranial-neural-crest migration and define a recognizable intellectual-disability syndrome". Am. J. Hum. Genet. 91 (6): 1122–7. doi:10.1016/j.ajhg.2012.10.013. PMC 3516611. PMID 23159249.
10. Online Mendelian Inheritance in Man (OMIM): 615009
11. "Domain Details Page".
12. Callaway E (2012). "Gene hunt is on for mental disability". Nature. 484 (7394): 302–3. Bibcode:2012Natur.484..302C. doi:10.1038/484302a. PMID 22517145.
13. "Treatment". pacs1.info. Archived from the original on 2016-03-04. Retrieved 2015-07-30.

Further reading

• Geyer M, Fackler OT, Peterlin BM (Jul 2001). "Structure--function relationships in HIV-1 Nef". EMBO Reports. 2 (7): 580–5. doi:10.1093/embo-reports/kve141. PMC 1083955. PMID 11463741.
• Leavitt SA, SchOn A, Klein JC, Manjappara U, Chaiken IM, Freire E (Feb 2004). "Interactions of HIV-1 proteins gp120 and Nef with cellular partners define a novel allosteric paradigm". Current Protein & Peptide Science. 5 (1): 1–8. doi:10.2174/1389203043486955. PMID 14965316.
• Joseph AM, Kumar M, Mitra D (Jan 2005). "Nef: "necessary and enforcing factor" in HIV infection". Current HIV Research. 3 (1): 87–94. doi:10.2174/1570162052773013. PMID 15638726.
• Wan L, Molloy SS, Thomas L, Liu G, Xiang Y, Rybak SL, Thomas G (Jul 1998). "PACS-1 defines a novel gene family of cytosolic sorting proteins required for trans-Golgi network localization". Cell. 94 (2): 205–16. doi:10.1016/S0092-8674(00)81420-8. PMID 9695949. S2CID 15027198.
• Hirosawa M, Nagase T, Ishikawa K, Kikuno R, Nomura N, Ohara O (Oct 1999). "Characterization of cDNA clones selected by the GeneMark analysis from size-fractionated cDNA libraries from human brain". DNA Research. 6 (5): 329–36. doi:10.1093/dnares/6.5.329. PMID 10574461.
• Piguet V, Wan L, Borel C, Mangasarian A, Demaurex N, Thomas G, Trono D (Mar 2000). "HIV-1 Nef protein binds to the cellular protein PACS-1 to downregulate class I major histocompatibility complexes". Nature Cell Biology. 2 (3): 163–7. doi:10.1038/35004038. PMC 1475706. PMID 10707087.
• Crump CM, Xiang Y, Thomas L, Gu F, Austin C, Tooze SA, Thomas G (May 2001). "PACS-1 binding to adaptors is required for acidic cluster motif-mediated protein traffic". The EMBO Journal. 20 (9): 2191–201. doi:10.1093/emboj/20.9.2191. PMC 125242. PMID 11331585.
• Williams M, Roeth JF, Kasper MR, Fleis RI, Przybycin CG, Collins KL (Dec 2002). "Direct binding of human immunodeficiency virus type 1 Nef to the major histocompatibility complex class I (MHC-I) cytoplasmic tail disrupts MHC-I trafficking". Journal of Virology. 76 (23): 12173–84. doi:10.1128/JVI.76.23.12173-12184.2002. PMC 136906. PMID 12414957.
• Blagoveshchenskaya AD, Thomas L, Feliciangeli SF, Hung CH, Thomas G (Dec 2002). "HIV-1 Nef downregulates MHC-I by a PACS-1- and PI3K-regulated ARF6 endocytic pathway". Cell. 111 (6): 853–66. doi:10.1016/S0092-8674(02)01162-5. PMID 12526811. S2CID 14835284.
• Scott GK, Gu F, Crump CM, Thomas L, Wan L, Xiang Y, Thomas G (Dec 2003). "The phosphorylation state of an autoregulatory domain controls PACS-1-directed protein traffic". The EMBO Journal. 22 (23): 6234–44. doi:10.1093/emboj/cdg596. PMC 291837. PMID 14633983.
• Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, Cohn MA, Cantley LC, Gygi SP (Aug 2004). "Large-scale characterization of HeLa cell nuclear phosphoproteins". Proceedings of the National Academy of Sciences of the United States of America. 101 (33): 12130–5. Bibcode:2004PNAS..10112130B. doi:10.1073/pnas.0404720101. PMC 514446. PMID 15302935.
• Köttgen M, Benzing T, Simmen T, Tauber R, Buchholz B, Feliciangeli S, Huber TB, Schermer B, Kramer-Zucker A, Höpker K, Simmen KC, Tschucke CC, Sandford R, Kim E, Thomas G, Walz G (Feb 2005). "Trafficking of TRPP2 by PACS proteins represents a novel mechanism of ion channel regulation". The EMBO Journal. 24 (4): 705–16. doi:10.1038/sj.emboj.7600566. PMC 549624. PMID 15692563.

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