PNKD

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.[5][6] Alternative splicing results in the transcription of three isoforms. The mouse ortholog is called brain protein 17 (Brp17).

PNKD
Identifiers
Aliases	PNKD, BRP17, DYT8, FPD1, KIPP1184, MR-1, MR1, PDC, PKND1, TAHCCP2, FKSG19, paroxysmal nonkinesigenic dyskinesia, PNKD1, MBL domain containing, MR-1S, PNKD metallo-beta-lactamase domain containing, R1
External IDs	OMIM: 609023 MGI: 1930773 HomoloGene: 75045 GeneCards: PNKD
Gene location (Human) Chr. Chromosome 2 (human)[1] Band 2q35 Start 218,270,392 bp[1] End 218,346,793 bp[1]
Gene location (Mouse) Chr. Chromosome 1 (mouse)[2] Band 1|1 C3 Start 74,284,930 bp[2] End 74,353,694 bp[2]
Gene ontology Molecular function • hydroxyacylglutathione hydrolase activity • GO:0001948 protein binding • hydrolase activity • metal ion binding Cellular component • cytoplasm • membrane • mitochondrion • cell nucleus Biological process • regulation of synaptic transmission, dopaminergic • methylglyoxal catabolic process to D-lactate via S-lactoyl-glutathione • negative regulation of neurotransmitter secretion • neuromuscular process controlling posture • regulation of dopamine metabolic process Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	25953	56695
Ensembl	ENSG00000127838	ENSMUSG00000026179
UniProt	Q8N490	Q69ZP3
RefSeq (mRNA)	NM_022572 NM_001077399 NM_015488	NM_001039509 NM_019999 NM_025580
RefSeq (protein)	NP_001070867 NP_056303 NP_072094	NP_001034598 NP_064383 NP_079856
Location (UCSC)	Chr 2: 218.27 – 218.35 Mb	Chr 1: 74.28 – 74.35 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Structure

This gene is located on chromosome 2 at the band 2q35 and contains 12 exons.[6] 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.[7][8] 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.[7] Moreover, PNKD-L localizes to the cell membrane, PNKD-S to the cytoplasm and nucleus, and PNKD-M to the mitochondrion.[9]

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.[7]

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.[10]

Clinical significance

Point mutations in PNKD exon 1 cause an inherited neurological movement disorder in human, paroxysmal non-kinesigenic dyskinesia.[6] Overexpression of PNKD has also been associated with multiple cancers, including pancreatic ductal adenocarcinoma,[11] gastric cancer,[12] ovarian cancer,[13] and breast cancer[8] 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.[8]

Interactions

PNKD has been shown to interact with:

• Rab3-interacting molecule (RIM)1[10]
• RIM2[10]

References

1. GRCh38: Ensembl release 89: ENSG00000127838 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000026179 - 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. 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.
6. "Entrez Gene: PNKD paroxysmal nonkinesiogenic dyskinesia".
7. 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.
8. 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. S2CID 38906043.
9. "PNKD - Probable hydrolase PNKD - Homo sapiens (Human) - PNKD gene & protein". www.uniprot.org. Retrieved 2016-07-25.
10. 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.
11. 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. S2CID 6019528.
12. 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.
13. 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. doi:10.3760/cma.j.issn.0253-3766.2012.03.004. PMID 22780969.