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{{for|the movement disorder also known as PNKD|Paroxysmal Nonkinesigenic Dyskinesia}}
{{PBB_Controls
{{Infobox_gene}}
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'''PNKD''' is the abbreviation for a human neurological movement disorder  '''paroxysmal nonkinesiogenic dyskinesia'''. Like many other human genetics disorders, PNKD also refers to the disease, the disease gene and the encoded protein. (PNKD) is a [[protein]] that in humans is encoded by the ''PNKD'' [[gene]].<ref name="pmid8659518">{{cite journal | vauthors = Fink JK, Rainer S, Wilkowski J, Jones SM, Kume A, Hedera P, Albin R, Mathay J, Girbach L, Varvil T, Otterud B, Leppert M | title = Paroxysmal dystonic choreoathetosis: tight linkage to chromosome 2q | journal = American Journal of Human Genetics | volume = 59 | issue = 1 | pages = 140–5 | date = July 1996 | pmid = 8659518 | pmc = 1915128 | doi =  }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: PNKD paroxysmal nonkinesiogenic dyskinesia| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=25953| accessdate = }}</ref> [[Alternative splicing]] results in the transcription of three [[protein isoform|isoforms]].  The mouse [[Homology (biology)#Orthology|ortholog]] is called brain protein 17 (Brp17).
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Structure ==
{{GNF_Protein_box
This gene is located on chromosome 2 at the band 2q35 and contains 12 [[exon]]s.<ref name="entrez" /> At least three isoforms of varying lengths (long, medium, and short) can be produced by alternative splicing of this gene. While the gene products of the long (PNKD-L) and medium (PNKD-M) isoforms contain the [[C-terminus|C-terminal]] [[metallo-beta-lactamase protein fold|β-lactamase domain]], the short (PNKD-S) isoform, commonly referred to as myofibrillogenesis regulator-1 (MR-1), contains only three exons and lacks homology to any known protein.<ref name="pmid21487022" /><ref name="Gong_2014">{{cite journal | vauthors = Gong Y, He H, Liu H, Zhang C, Zhao W, Shao RG | title = Phosphorylation of myofibrillogenesis regulator-1 activates the MAPK signaling pathway and induces proliferation and migration in human breast cancer MCF7 cells | journal = FEBS Letters | volume = 588 | issue = 17 | pages = 2903–10 | date = August 2014 | pmid = 25066297 | doi = 10.1016/j.febslet.2014.07.018 }}</ref> These isoforms also differ in their tissue-specific expression and [[subcellular localization]]. Specifically, PNKD-L is only expressed in the [[central nervous system]] whereas PNKD-M and PNKD-S are ubiquitously expressed across tissues.<ref name="pmid21487022" /> Moreover, PNKD-L localizes to the [[cell membrane]], PNKD-S to the [[cytoplasm]] and [[Cell nucleus|nucleus]], and PNKD-M to the [[mitochondrion]].<ref>{{Cite web|url=http://www.uniprot.org/uniprot/Q8N490|title=PNKD - Probable hydrolase PNKD - Homo sapiens (Human) - PNKD gene & protein|website=www.uniprot.org|access-date=2016-07-25}}</ref>
| image = 
| image_source = 
| PDB =
| Name = Paroxysmal nonkinesiogenic dyskinesia
| HGNCid = 9153
| Symbol = PNKD
| AltSymbols =; MR1; PDC; BRP17; DKFZp564N1362; DYT8; FKSG19; FPD1; KIAA1184; KIPP1184; MGC31943; MR-1; TAHCCP2
| OMIM = 609023
| ECnumber = 
| Homologene = 75045
| MGIid = 1930773
| Function = {{GNF_GO|id=GO:0016787 |text = hydrolase activity}}
| Component = {{GNF_GO|id=GO:0005635 |text = nuclear envelope}}
| Process =  
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 25953
    | Hs_Ensembl = ENSG00000127838
    | Hs_RefseqProtein = NP_001070867
    | Hs_RefseqmRNA = NM_001077399
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 2
    | Hs_GenLoc_start = 218843359
    | Hs_GenLoc_end = 218919756
    | Hs_Uniprot = 
    | Mm_EntrezGene = 56695
    | Mm_Ensembl = ENSMUSG00000026179
    | Mm_RefseqmRNA = NM_001039509
    | Mm_RefseqProtein = NP_001034598
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 1
    | Mm_GenLoc_start = 74218241
    | Mm_GenLoc_end = 74286899
    | Mm_Uniprot = 
  }}
}}
'''Paroxysmal nonkinesiogenic dyskinesia''', also known as '''PNKD''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: PNKD paroxysmal nonkinesiogenic dyskinesia| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=25953| accessdate = }}</ref>


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== Function ==
{{PBB_Summary
| section_title =  
| summary_text =  
}}


==References==
The function of PNKD proteins are unknown but the long and medium isoforms of PNKD contain a conserved [[metallo-beta-lactamase protein fold|β-lactamase domain]] which suggest it may function as an [[enzyme]]. The closest mammalian homolog to PNKD is [[HAGH]], an enzyme involves in a two-step reaction to hydrolyze SLG and produce D-lactic acid and reduced GSH. However, the hydrolytic activity of PNKD is minimal.<ref name="pmid21487022">{{cite journal | vauthors = Shen Y, Lee HY, Rawson J, Ojha S, Babbitt P, Fu YH, Ptácek LJ | title = Mutations in PNKD causing paroxysmal dyskinesia alters protein cleavage and stability | journal = Human Molecular Genetics | volume = 20 | issue = 12 | pages = 2322–32 | date = June 2011 | pmid = 21487022 | pmc = 3098736 | doi = 10.1093/hmg/ddr125 }}</ref>
{{reflist|2}}
==Further reading==
{{refbegin | 2}}
{{PBB_Further_reading
| citations =
*{{cite journal  | author=Sparkes RS, Lee RH, Shinohara T, ''et al.'' |title=Assignment of the phosducin (PDC) gene to human chromosome 1q25-1q32.1 by somatic cell hybridization and in situ hybridization. |journal=Genomics |volume=18 |issue= 2 |pages= 426-8 |year= 1994 |pmid= 8288249 |doi= 10.1006/geno.1993.1490 }}
*{{cite journal  | author=Fouad GT, Servidei S, Durcan S, ''et al.'' |title=A gene for familial paroxysmal dyskinesia (FPD1) maps to chromosome 2q. |journal=Am. J. Hum. Genet. |volume=59 |issue= 1 |pages= 135-9 |year= 1996 |pmid= 8659517 |doi=  }}
*{{cite journal  | author=Fink JK, Rainer S, Wilkowski J, ''et al.'' |title=Paroxysmal dystonic choreoathetosis: tight linkage to chromosome 2q. |journal=Am. J. Hum. Genet. |volume=59 |issue= 1 |pages= 140-5 |year= 1996 |pmid= 8659518 |doi=  }}
*{{cite journal  | author=Raskind WH, Bolin T, Wolff J, ''et al.'' |title=Further localization of a gene for paroxysmal dystonic choreoathetosis to a 5-cM region on chromosome 2q34. |journal=Hum. Genet. |volume=102 |issue= 1 |pages= 93-7 |year= 1998 |pmid= 9490305 |doi=  }}
*{{cite journal  | author=Hirosawa M, Nagase T, Ishikawa K, ''et al.'' |title=Characterization of cDNA clones selected by the GeneMark analysis from size-fractionated cDNA libraries from human brain. |journal=DNA Res. |volume=6 |issue= 5 |pages= 329-36 |year= 2000 |pmid= 10574461 |doi= }}
*{{cite journal  | author=Hartley JL, Temple GF, Brasch MA |title=DNA cloning using in vitro site-specific recombination. |journal=Genome Res. |volume=10 |issue= 11 |pages= 1788-95 |year= 2001 |pmid= 11076863 |doi=  }}
*{{cite journal  | author=Simpson JC, Wellenreuther R, Poustka A, ''et al.'' |title=Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing. |journal=EMBO Rep. |volume=1 |issue= 3 |pages= 287-92 |year= 2001 |pmid= 11256614 |doi= 10.1093/embo-reports/kvd058 }}
*{{cite journal  | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
*{{cite journal  | author=Clark HF, Gurney AL, Abaya E, ''et al.'' |title=The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment. |journal=Genome Res. |volume=13 |issue= 10 |pages= 2265-70 |year= 2003 |pmid= 12975309 |doi= 10.1101/gr.1293003 }}
*{{cite journal  | author=Li TB, Liu XH, Feng S, ''et al.'' |title=Characterization of MR-1, a novel myofibrillogenesis regulator in human muscle. |journal=Acta Biochim. Biophys. Sin. (Shanghai) |volume=36 |issue= 6 |pages= 412-8 |year= 2005 |pmid= 15188056 |doi=  }}
*{{cite journal | author=Liu M, Liu Y, Cheng J, ''et al.'' |title=Transactivating effect of hepatitis C virus core protein: a suppression subtractive hybridization study. |journal=World J. Gastroenterol. |volume=10 |issue= 12 |pages= 1746-9 |year= 2004 |pmid= 15188498 |doi=  }}
*{{cite journal  | author=Wiemann S, Arlt D, Huber W, ''et al.'' |title=From ORFeome to biology: a functional genomics pipeline. |journal=Genome Res. |volume=14 |issue= 10B |pages= 2136-44 |year= 2004 |pmid= 15489336 |doi= 10.1101/gr.2576704 }}
*{{cite journal  | author=Lee HY, Xu Y, Huang Y, ''et al.'' |title=The gene for paroxysmal non-kinesigenic dyskinesia encodes an enzyme in a stress response pathway. |journal=Hum. Mol. Genet. |volume=13 |issue= 24 |pages= 3161-70 |year= 2005 |pmid= 15496428 |doi= 10.1093/hmg/ddh330 }}
*{{cite journal  | author=Diniz SC, Taciro MK, Gomez JG, da Cruz Pradella JG |title=High-cell-density cultivation of Pseudomonas putida IPT 046 and medium-chain-length polyhydroxyalkanoate production from sugarcane carbohydrates. |journal=Appl. Biochem. Biotechnol. |volume=119 |issue= 1 |pages= 51-70 |year= 2005 |pmid= 15496728 |doi=  }}
*{{cite journal  | author=Chen DH, Matsushita M, Rainier S, ''et al.'' |title=Presence of alanine-to-valine substitutions in myofibrillogenesis regulator 1 in paroxysmal nonkinesigenic dyskinesia: confirmation in 2 kindreds. |journal=Arch. Neurol. |volume=62 |issue= 4 |pages= 597-600 |year= 2005 |pmid= 15824259 |doi= 10.1001/archneur.62.4.597 }}
*{{cite journal  | author=Rual JF, Venkatesan K, Hao T, ''et al.'' |title=Towards a proteome-scale map of the human protein-protein interaction network. |journal=Nature |volume=437 |issue= 7062 |pages= 1173-8 |year= 2005 |pmid= 16189514 |doi= 10.1038/nature04209 }}
*{{cite journal  | author=Mehrle A, Rosenfelder H, Schupp I, ''et al.'' |title=The LIFEdb database in 2006. |journal=Nucleic Acids Res. |volume=34 |issue= Database issue |pages= D415-8 |year= 2006 |pmid= 16381901 |doi= 10.1093/nar/gkj139 }}
*{{cite journal  | author=Stefanova E, Djarmati A, Momcilović D, ''et al.'' |title=Clinical characteristics of paroxysmal nonkinesigenic dyskinesia in Serbian family with Myofibrillogenesis regulator 1 gene mutation. |journal=Mov. Disord. |volume=21 |issue= 11 |pages= 2010-5 |year= 2007 |pmid= 16972263 |doi= 10.1002/mds.21095 }}
}}
{{refend}}


{{protein-stub}}
The long form of PNKD is neuronal specific and encodes a synaptic protein that localizes dominantly to the pre-synaptic membrane. Post-synaptic area and vesicular structure also occasionally has PNKD long form. PNKD long form interacts with pre-synaptic protein RIM and inhibits synaptic exocytosis. PNKD with disease mutations is less effective in inhibition thus the synaptic release is increased. This would cause excessive neurotransmitter release in the brain and maybe the root cause for triggering epilepsy in PNKD patients.<ref name="Shen_2015">{{cite journal | vauthors = Shen Y, Ge WP, Li Y, Hirano A, Lee HY, Rohlmann A, Missler M, Tsien RW, Jan LY, Fu YH, Ptáček LJ | title = Protein mutated in paroxysmal dyskinesia interacts with the active zone protein RIM and suppresses synaptic vesicle exocytosis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 112 | issue = 10 | pages = 2935–41 | date = March 2015 | pmid = 25730884 | doi = 10.1073/pnas.1501364112 | pmc=4364199}}</ref>
{{WikiDoc Sources}}
 
== Clinical significance ==
 
Point mutations in PNKD exon 1 cause an inherited neurological movement disorder in human, [[dystonia|paroxysmal non-kinesigenic dyskinesia]].<ref name="entrez"/> Overexpression of PNKD has also been associated with multiple cancers, including [[pancreatic ductal adenocarcinoma]],<ref>{{cite journal | vauthors = Zhao CY, Guo ZJ, Dai SM, Zhang Y, Zhou JJ | title = Clinicopathological and prognostic significance of myofibrillogenesis regulator-1 protein expression in pancreatic ductal adenocarcinoma | journal = Tumour Biology | volume = 34 | issue = 5 | pages = 2983–7 | date = October 2013 | pmid = 23696030 | doi = 10.1007/s13277-013-0862-4 }}</ref> [[gastric cancer]],<ref>{{cite journal | vauthors = Guo J, Dong B, Ji JF, Wu AW | title = Myofibrillogenesis regulator-1 overexpression is associated with poor prognosis of gastric cancer patients | journal = World Journal of Gastroenterology | volume = 18 | issue = 38 | pages = 5434–41 | date = October 2012 | pmid = 23082061 | pmc = 3471113 | doi = 10.3748/wjg.v18.i38.5434 }}</ref> [[ovarian cancer]],<ref>{{cite journal | vauthors = Lu RQ, Sun M, Gao X, Guo L | title = [Expression of a novel biomarker, MR-1S, in ovarian carcinoma and its biological significance] | journal = Zhonghua Zhong Liu Za Zhi [Chinese Journal of Oncology] | volume = 34 | issue = 3 | pages = 176–81 | date = March 2012 | pmid = 22780969 }}</ref> and [[breast cancer]]<ref name="Gong_2014" /> and may serve as a therapeutic target for treating these cancers or a [[biomarker]] for assessing patient outcome. The signaling pathways involved may vary depending on the cancer. For instance, in human breast cancer (MCF7) cells, PNKD may promote tumor cell proliferation by activating the [[MAPK/ERK pathway|MEK/ERK]] signaling pathway, while in human hepatoma (HepG2) cells, PNKD may operate through the [[Akt/PKB signaling pathway|MLC2/FAK/AKT]] pathway.<ref name="Gong_2014" />
 
== Interactions ==
PNKD has been shown to [[Protein-protein interaction|interact]] with:
* Rab3-interacting molecule (RIM)1<ref name="Shen_2015" />
* RIM2<ref name="Shen_2015" />
 
== References ==
{{reflist|33em}}

Revision as of 22:16, 30 October 2017

For the movement disorder also known as PNKD, see Paroxysmal Nonkinesigenic Dyskinesia.
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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human

PNKD is the abbreviation for a human neurological movement disorder paroxysmal nonkinesiogenic dyskinesia. Like many other human genetics disorders, PNKD also refers to the disease, the disease gene and the encoded protein. (PNKD) is a protein that in humans is encoded by the PNKD gene.[1][2] Alternative splicing results in the transcription of three isoforms. The mouse ortholog is called brain protein 17 (Brp17).

Structure

This gene is located on chromosome 2 at the band 2q35 and contains 12 exons.[2] At least three isoforms of varying lengths (long, medium, and short) can be produced by alternative splicing of this gene. While the gene products of the long (PNKD-L) and medium (PNKD-M) isoforms contain the C-terminal β-lactamase domain, the short (PNKD-S) isoform, commonly referred to as myofibrillogenesis regulator-1 (MR-1), contains only three exons and lacks homology to any known protein.[3][4] These isoforms also differ in their tissue-specific expression and subcellular localization. Specifically, PNKD-L is only expressed in the central nervous system whereas PNKD-M and PNKD-S are ubiquitously expressed across tissues.[3] Moreover, PNKD-L localizes to the cell membrane, PNKD-S to the cytoplasm and nucleus, and PNKD-M to the mitochondrion.[5]

Function

The function of PNKD proteins are unknown but the long and medium isoforms of PNKD contain a conserved β-lactamase domain which suggest it may function as an enzyme. The closest mammalian homolog to PNKD is HAGH, an enzyme involves in a two-step reaction to hydrolyze SLG and produce D-lactic acid and reduced GSH. However, the hydrolytic activity of PNKD is minimal.[3]

The long form of PNKD is neuronal specific and encodes a synaptic protein that localizes dominantly to the pre-synaptic membrane. Post-synaptic area and vesicular structure also occasionally has PNKD long form. PNKD long form interacts with pre-synaptic protein RIM and inhibits synaptic exocytosis. PNKD with disease mutations is less effective in inhibition thus the synaptic release is increased. This would cause excessive neurotransmitter release in the brain and maybe the root cause for triggering epilepsy in PNKD patients.[6]

Clinical significance

Point mutations in PNKD exon 1 cause an inherited neurological movement disorder in human, paroxysmal non-kinesigenic dyskinesia.[2] Overexpression of PNKD has also been associated with multiple cancers, including pancreatic ductal adenocarcinoma,[7] gastric cancer,[8] ovarian cancer,[9] and breast cancer[4] and may serve as a therapeutic target for treating these cancers or a biomarker for assessing patient outcome. The signaling pathways involved may vary depending on the cancer. For instance, in human breast cancer (MCF7) cells, PNKD may promote tumor cell proliferation by activating the MEK/ERK signaling pathway, while in human hepatoma (HepG2) cells, PNKD may operate through the MLC2/FAK/AKT pathway.[4]

Interactions

PNKD has been shown to interact with:

  • Rab3-interacting molecule (RIM)1[6]
  • RIM2[6]

References

  1. ↑ Fink JK, Rainer S, Wilkowski J, Jones SM, Kume A, Hedera P, Albin R, Mathay J, Girbach L, Varvil T, Otterud B, Leppert M (July 1996). "Paroxysmal dystonic choreoathetosis: tight linkage to chromosome 2q". American Journal of Human Genetics. 59 (1): 140–5. PMC 1915128. PMID 8659518.
  2. ↑ 2.0 2.1 2.2 "Entrez Gene: PNKD paroxysmal nonkinesiogenic dyskinesia".
  3. ↑ 3.0 3.1 3.2 Shen Y, Lee HY, Rawson J, Ojha S, Babbitt P, Fu YH, Ptácek LJ (June 2011). "Mutations in PNKD causing paroxysmal dyskinesia alters protein cleavage and stability". Human Molecular Genetics. 20 (12): 2322–32. doi:10.1093/hmg/ddr125. PMC 3098736. PMID 21487022.
  4. ↑ 4.0 4.1 4.2 Gong Y, He H, Liu H, Zhang C, Zhao W, Shao RG (August 2014). "Phosphorylation of myofibrillogenesis regulator-1 activates the MAPK signaling pathway and induces proliferation and migration in human breast cancer MCF7 cells". FEBS Letters. 588 (17): 2903–10. doi:10.1016/j.febslet.2014.07.018. PMID 25066297.
  5. ↑ "PNKD - Probable hydrolase PNKD - Homo sapiens (Human) - PNKD gene & protein". www.uniprot.org. Retrieved 2016-07-25.
  6. ↑ 6.0 6.1 6.2 Shen Y, Ge WP, Li Y, Hirano A, Lee HY, Rohlmann A, Missler M, Tsien RW, Jan LY, Fu YH, Ptáček LJ (March 2015). "Protein mutated in paroxysmal dyskinesia interacts with the active zone protein RIM and suppresses synaptic vesicle exocytosis". Proceedings of the National Academy of Sciences of the United States of America. 112 (10): 2935–41. doi:10.1073/pnas.1501364112. PMC 4364199. PMID 25730884.
  7. ↑ Zhao CY, Guo ZJ, Dai SM, Zhang Y, Zhou JJ (October 2013). "Clinicopathological and prognostic significance of myofibrillogenesis regulator-1 protein expression in pancreatic ductal adenocarcinoma". Tumour Biology. 34 (5): 2983–7. doi:10.1007/s13277-013-0862-4. PMID 23696030.
  8. ↑ Guo J, Dong B, Ji JF, Wu AW (October 2012). "Myofibrillogenesis regulator-1 overexpression is associated with poor prognosis of gastric cancer patients". World Journal of Gastroenterology. 18 (38): 5434–41. doi:10.3748/wjg.v18.i38.5434. PMC 3471113. PMID 23082061.
  9. ↑ Lu RQ, Sun M, Gao X, Guo L (March 2012). "[Expression of a novel biomarker, MR-1S, in ovarian carcinoma and its biological significance]". Zhonghua Zhong Liu Za Zhi [Chinese Journal of Oncology]. 34 (3): 176–81. PMID 22780969.
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