PACS1 explained

Phosphofurin acidic cluster sorting protein 1, also known as PACS-1, is a protein that in humans is encoded by the PACS1 gene.^{[1] [2] [3]}

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.^[4]

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.^[5]

Prevalence and diagnosis

The first two cases were identified in early 2011 by doctors in the Netherlands.^[5] As of late 2014, there were 20 cases identified worldwide.^[6]

Diagnosis is typically done using full genome or exome sequencing.^[7] 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.^[8]

• 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

Further reading

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

Notes and References

1. Stove V, Naessens E, Stove C, Swigut T, Plum J, Verhasselt B . 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 . Oct 2003 . 12855553 . 10.1182/blood-2003-03-0833 . free .
2. Hinners I, Wendler F, Fei H, Thomas L, Thomas G, Tooze SA . AP-1 recruitment to VAMP4 is modulated by phosphorylation-dependent binding of PACS-1 . EMBO Reports . 4 . 12 . 1182–9 . Dec 2003 . 14608369 . 1326413 . 10.1038/sj.embor.7400018 .
3. Web site: Entrez Gene: PACS1 phosphofurin acidic cluster sorting protein 1.
4. Wan L, Molloy SS, Thomas L, Liu G, Xiang Y, Rybak SL, Thomas G . PACS-1 defines a novel gene family of cytosolic sorting proteins required for trans-Golgi network localization . Cell . 94 . 2 . 205–16 . Jul 1998 . 9695949 . 10.1016/S0092-8674(00)81420-8 . 15027198 . free .
5. 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 . 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 . 2012 . 23159249 . 3516611 . 10.1016/j.ajhg.2012.10.013 .
6. Web site: Domain Details Page .
7. Callaway E . Gene hunt is on for mental disability . Nature . 484 . 7394 . 302–3 . 2012 . 22517145 . 10.1038/484302a . 2012Natur.484..302C . free .
8. Web site: Treatment . pacs1.info . 2015-07-30 . 2016-03-04 . https://web.archive.org/web/20160304223433/http://www.pacs1.info/treatment . dead .