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{{Short description|Protein-coding gene in the species Homo sapiens}}
{{GNF_Protein_box/sandbox
{{Infobox gene}}
| name = PBB/9353
| Name = PLEKHA7 (pleckstrin homology domain containing, family A member 7)
'''PLEKHA7''' (Pleckstrin homology domain-containing family A member 7) is an [[adherens junction]] (AJ) protein, involved in the junction's integrity and stability.
| HGNCid = 27049
| MGIid = 2445094
| Symbol = PLEKHA7
| AltSymbols =; DKFZp686M22243
| OMIM = 612686
| Homologene = 52172
| Function = {{GNF_GO|id=GO:0070097 |text =delta-catenin binding}}
| Component = {{GNF_GO|id=GO:0030054|text = cell junction}} {{GNF_GO|id=GO:0005813 |text = centrosome}} {{GNF_GO|id=GO:0005737 |text = cytoplasm}} {{GNF_GO|id=GO:0005634 |text = nucleus}} {{GNF_GO|id=GO:0005915|text = zonula adherents}}
| Process = {{GNF_GO|id=GO:0090136 |text = epithelial cell-cell adhesion}} {{GNF_GO|id=GO:0045218 |text = zonula adherens maintenance}}
| Hs_EntrezGene = 144100
| Hs_Ensembl = ENSG00000166689
| Hs_RefseqmRNA = NM_175058.4
| Hs_RefseqProtein = NP_778228.3
| Hs_GenLoc_db = hg19
| Hs_GenLoc_chr = 11
| Hs_GenLoc_start = 16809207
| Hs_GenLoc_end = 16838962
| Hs_Uniprot = Q61Q23
| Mm_EntrezGene = 233765
| Mm_Ensembl = ENSMUSG00000045659
| Mm_RefseqmRNA = NM_172743.2
| Mm_RefseqProtein = NP_766331.1
| Mm_GenLoc_db = mm9
| Mm_GenLoc_chr = 7
| Mm_GenLoc_start = 4123267632
| Mm_GenLoc_end = 123381290
| Mm_Uniprot = Q3UIL6}}


== History ==
'''PLEKHA7''' (Pleckstrin homology domain-containing family A member 7) is an [[adherens junction]] (AJ) protein, discovered in [[Masatoshi Takeichi]]’s lab while looking for potential binding partners for the N-terminal region of [[p120-catenin]]. PLEKHA7 was identified by mass spectrometry in [[lysate]]s of human intestinal carcinoma ([[Caco-2]]) cells in a [[Glutathione S-transferase#GST-tags and the GST pull-down assay|GST-pull down]] using N-terminal [[Glutathione S-transferase|GST]]-[[fusion protein|fusion]] p120 catenin as bait.
The protein was discovered in [[Masatoshi Takeichi]]’s lab while looking for potential binding partners for the N-terminal region of [[p120-catenin|p120]]. PLEKHA7 was identified by mass spectrometry in [[lysate]]s of human intestinal carcinoma ([[Caco-2]]) cells in a [[Glutathione S-transferase#GST-tags and the GST pull-down assay|GST-pull down]] using N-terminal [[Glutathione S-transferase|GST]]-[[fusion protein|fusion]] p120 catenin as bait.<ref name="pmid19041755">{{cite journal | vauthors = Meng W, Mushika Y, Ichii T, Takeichi M | title = Anchorage of microtubule minus ends to adherens junctions regulates epithelial cell-cell contacts | journal = Cell | volume = 135 | issue = 5 | pages = 948–59 | date = November 2008 | pmid = 19041755 | doi = 10.1016/j.cell.2008.09.040 | s2cid = 14503414 | doi-access = free }}</ref> It was also independently discovered in [[Sandra Citi]]’s group as a protein interacting with globular head domain of the Paracingulin in a yeast [[two-hybrid screen]]. PLEKHA7 localizes at epithelial zonular AJs.<ref name="pmid20808826">{{cite journal | vauthors = Pulimeno P, Bauer C, Stutz J, Citi S | title = PLEKHA7 is an adherens junction protein with a tissue distribution and subcellular localization distinct from ZO-1 and E-cadherin | journal = PLOS ONE | volume = 5 | issue = 8 | pages = e12207 | date = August 2010 | pmid = 20808826 | pmc = 2924883 | doi = 10.1371/journal.pone.0012207 | bibcode = 2010PLoSO...512207P | doi-access = free }}</ref>
<ref name="pmid19041755">{{cite journal | title=Anchorage of microtubule minus ends to adherens junctions regulates epithelial cell-cell contacts. | author=Meng W, Mushika Y, Ichii T, Takeichi M. | journal=Cell |date=Nov 2008 | volume=135 | issue=5 | pages=948-59 | doi=10.1016/j.cell.2008.09.040 | PMID=19041755}}</ref>
PLEKHA7 was also independently discovered in Sandra Citi’s group as a protein interacting with globular head domain of the Paracingulin in a yeast [[two-hybrid screen]]. PLEKHA7 localizes at epithelial zonular AJs.<ref name="pmid20808826">{{cite journal | title=PLEKHA7 is an adherens junction protein with a tissue distribution and subcellular localization distinct from ZO-1 and E-cadherin. | author=Pulimeno P, Bauer C, Stutz J, Citi S. | journal=PLoS ONE |date=Aug 2010 | volume=5 | issue=8 | pages=e12207 | doi=10.1371/journal.pone.0012207 | PMID=20808826 | pmc=2924883}}</ref>


== Structure ==
== Structure ==
Line 41: Line 13:
== Protein-protein interactions ==
== Protein-protein interactions ==


In vitro interaction studies were pursued to map the interaction(s) of PLEKHA 7 with p120 Catenin (residues 538-696), Nezha (residues 680-821), [[paracingulin]] (residues 620-769) and [[Afadin]] (residues 120-374).<ref name="pmid23990464">{{cite journal | title=Binding between the junctional proteins afadin and PLEKHA7 and implication in the formation of adherens junction in epithelial cells | author=Kurita S, Yamada T, Rikitsu E, Ikeda W, Takai Y | journal=J Biol Chem |date=Oct 2013 | volume=288 | issue=41 | pages=29356-68 | doi=10.1074/jbc.M113.453464 | PMID=23990464}}</ref> Unlike most other AJ proteins, but similar to afadin, PLEKHA7 is exclusively detected in the zonular apical part of AJ, but not in the “puncta adherentia” along lateral membranes of the epithelial cells. Cellular localization and tissue distribution of PLEKHA7 has been confirmed by Immunoelectron microscopy (Immuno-EM) of wild type and knock down intestinal epithelial tissues.<ref name="pmid20808826"/>
In vitro interaction studies were pursued to map the interaction(s) of PLEKHA7 with [[p120-catenin|p120]] (residues 538-696), Nezha ([[CAMSAP3]]) (residues 680-821), [[paracingulin]] (residues 620-769) and [[Afadin]] (residues 120-374).<ref name="pmid23990464">{{cite journal | vauthors = Kurita S, Yamada T, Rikitsu E, Ikeda W, Takai Y | title = Binding between the junctional proteins afadin and PLEKHA7 and implication in the formation of adherens junction in epithelial cells | journal = The Journal of Biological Chemistry | volume = 288 | issue = 41 | pages = 29356–68 | date = October 2013 | pmid = 23990464 | pmc = 3795237 | doi = 10.1074/jbc.M113.453464 | doi-access = free }}</ref> The protein PDZD11 was identified as a protein interacting through its N-terminal region with the N-terminal WW domain of PLEKHA7, based on 2-hybrid screen and analysis of PLEKHA7 immunoprecipitates<ref>{{cite journal | vauthors = Guerrera D, Shah J, Vasileva E, Sluysmans S, Méan I, Jond L, Poser I, Mann M, Hyman AA, Citi S | title = PLEKHA7 Recruits PDZD11 to Adherens Junctions to Stabilize Nectins | journal = The Journal of Biological Chemistry | volume = 291 | issue = 21 | pages = 11016–29 | date = May 2016 | pmid = 27044745 | pmc = 4900252 | doi = 10.1074/jbc.M115.712935 | doi-access = free }}</ref> Unlike most other AJ proteins, but similar to afadin, PLEKHA7 is exclusively detected in the zonular apical part of AJ, but not in the “puncta adherentia” along lateral membranes of the epithelial cells.<ref name="pmid20808826"/> Cellular localization and tissue distribution of PLEKHA7 has been confirmed by Immunoelectron microscopy (Immuno-EM) of wild type and knock down intestinal epithelial tissues.<ref name="pmid20808826"/>


== Function ==
== Function ==


One function of PLEKHA7 is to contribute to integrity and stability of the zonula adherens junctions by linking the [[E-cadherin]]/p120 complex to the minus ends of [[microtubules]] (MTs) through Nezha.<ref name="pmid19041755"/> The PLEKHA7-Nezha- MTs complex allows transport of the [[KIFC3]] (a minus end directed motor) to the AJ. However, in Eph4 cell line, PLEKHA7 is recruited to E-cadherin based AJ by Afadin, independently of p120.<ref name="pmid23990464"/> PLEKHA7 knockdown studies in Madin-Darby canine kidney (MDCK) cells indicated its requirement for the AJ localization of paracingulin.<ref name="pmid21454477">{{cite journal | title=A role for ZO-1 and PLEKHA7 in recruiting paracingulin to tight and adherens junctions of epithelial cells. | author=Pulimeno P, Paschoud S, Citi S. | journal=J. Biol Chem. |date=May 2011 | volume=286 | issue=19 | pages=16743-50. | doi=10.1074/jbc.M111.230862 | PMID=21454477 | pmc=3089516}}</ref> Furthermore, the PLEKHA7 homolog in [[zebrafish]], Hadp1, is required for proper heart function and [[morphogenesis]] in embryo, regulating the intracellular {{chem|Ca|2+}} dynamics through the [[phosphatidylinositol 4-kinase]] (PIK4) pathway.<ref name="pmid21628396">{{cite journal | title=Hadp1, a newly identified pleckstrin homology domain protein, is required for cardiac contractility in zebrafish. | author=Wythe JD, Jurynec MJ, Urness LD, Jones CA, Sabeh MK, Werdich AA, Sato M, Yost HJ, Grunwald DJ, Macrae CA, Li DY. | journal=Dis Model Mech. |date=Sep 2011 | volume=4 | issue=5 | pages=607-21. | doi=10.1242/dmm.002204 | PMID=21628396 | pmc=3180224}}</ref>
The first identified function of PLEKHA7 was is to contribute to integrity and stability of the [[zonula adherens]] junctions by linking the [[E-cadherin]]/p120 complex to the minus ends of [[microtubules]] (MTs) through Nezha (CAMSAP3).<ref name="pmid19041755"/> The PLEKHA7-Nezha- MTs complex allows transport of the [[KIFC3]] (a minus end directed motor) to the AJ. However, in Eph4 cell line, PLEKHA7 is recruited to E-cadherin based AJ by Afadin, independently of p120.<ref name="pmid23990464"/> PLEKHA7 knockdown studies in Madin-Darby canine kidney ([[MDCK]]) cells indicated its requirement for the AJ localization of paracingulin.<ref name="pmid21454477">{{cite journal | vauthors = Pulimeno P, Paschoud S, Citi S | title = A role for ZO-1 and PLEKHA7 in recruiting paracingulin to tight and adherens junctions of epithelial cells | journal = The Journal of Biological Chemistry | volume = 286 | issue = 19 | pages = 16743–50 | date = May 2011 | pmid = 21454477 | pmc = 3089516 | doi = 10.1074/jbc.M111.230862 | doi-access = free }}</ref> Furthermore, the PLEKHA7 homolog in [[zebrafish]], Hadp1, is required for proper heart function and [[morphogenesis]] in embryo, regulating the intracellular {{chem|Ca|2+}} dynamics through the [[phosphatidylinositol 4-kinase]] (PIK4) pathway.<ref name="pmid21628396">{{cite journal | vauthors = Wythe JD, Jurynec MJ, Urness LD, Jones CA, Sabeh MK, Werdich AA, Sato M, Yost HJ, Grunwald DJ, Macrae CA, Li DY | title = Hadp1, a newly identified pleckstrin homology domain protein, is required for cardiac contractility in zebrafish | journal = Disease Models & Mechanisms | volume = 4 | issue = 5 | pages = 607–21 | date = September 2011 | pmid = 21628396 | pmc = 3180224 | doi = 10.1242/dmm.002204 }}</ref>


In 2015, researchers discovered that PLEKHA7 recruits the so-called "microprocessor complex" (association of [[Drosha|DROSHA]] and [[DGCR8]] proteins) to a growth-inhibiting site (apical [[zonula adherens]]) in [[epithelial cells]] instead of sites at basolateral areas of cell–cell contact containing [[tyrosine]]-[[phosphorylated]] [[p120-catenin|p120]] and active [[Proto-oncogene tyrosine-protein kinase Src|Src]]. Loss of PLEKHA7 disrupts [[miRNA]]s regulation, causing [[tumorigenic]] signaling and growth. Restoring normal miRNA levels in tumor cells can reverse that aberrant signaling.<ref>{{cite journal |date=24 August 2015 |title=Distinct E-cadherin-based complexes regulate cell behaviour through miRNA processing or Src and p120 catenin activity |doi=10.1038/ncb3227|journal=Nature Cell Biology|access-date=26 August 2015}}</ref><ref>{{cite web |url=http://newsnetwork.mayoclinic.org/discussion/mayo-clinic-researchers-find-new-code-that-makes-reprogramming-of-cancer-cells-possible/ |title=Mayo Clinic researchers find new code that makes reprogramming of cancer cells possible}}</ref><ref>[http://www.nature.com/ncb/journal/vaop/ncurrent/full/ncb3227.html Distinct E-cadherin-based complexes regulate cell behaviour through miRNA processing or Src and p120 catenin activity. Kourtidis et al. 2015]</ref>In 2015 it was also discovered that PLEKHA7 has a role in controlling susceptibility to Staphylococcus aureus alpha-toxin <ref>{{Cite journal|title = The adherens junctions control susceptibility to Staphylococcus aureus α-toxin|url = http://www.ncbi.nlm.nih.gov/pubmed/26489655|journal = Proceedings of the National Academy of Sciences of the United States of America|date = 2015-10-21|issn = 1091-6490|pmid = 26489655|doi = 10.1073/pnas.1510265112|first = Lauren M.|last = Popov|first2 = Caleb D.|last2 = Marceau|first3 = Philipp M.|last3 = Starkl|first4 = Jennifer H.|last4 = Lumb|first5 = Jimit|last5 = Shah|first6 = Diego|last6 = Guerrera|first7 = Rachel L.|last7 = Cooper|first8 = Christina|last8 = Merakou|first9 = Donna M.|last9 = Bouley}}</ref>Cells lacking PLEKHA7 are injured by the toxin, but recover after intoxication. Mice knockout for PLEKHA7 are viable and fertile, and when infected with methycillin-resistant S. aureus USA300 LAC strain they show a decreased disease severity in both skin infection and lethal pneumonia, thus identifying PLEKHA7 as a potential nonessential host target to reduce S. aureus virulence during epithelial infections <ref>{{Cite journal|title = The adherens junctions control susceptibility to Staphylococcus aureus α-toxin|url = http://www.ncbi.nlm.nih.gov/pubmed/26489655|journal = Proceedings of the National Academy of Sciences of the United States of America|date = 2015-10-21|issn = 1091-6490|pmid = 26489655|doi = 10.1073/pnas.1510265112|first = Lauren M.|last = Popov|first2 = Caleb D.|last2 = Marceau|first3 = Philipp M.|last3 = Starkl|first4 = Jennifer H.|last4 = Lumb|first5 = Jimit|last5 = Shah|first6 = Diego|last6 = Guerrera|first7 = Rachel L.|last7 = Cooper|first8 = Christina|last8 = Merakou|first9 = Donna M.|last9 = Bouley}}</ref>.
In 2015, researchers discovered that PLEKHA7 recruits the so-called [[microprocessor complex]] (association of [[Drosha]] and [[DGCR8]] proteins) to a growth-inhibiting site (apical [[zonula adherens]]) in [[epithelial cells]] instead of sites at basolateral areas of cell–cell contact containing [[tyrosine]]-[[phosphorylated]] [[p120-catenin|p120]] and active [[Proto-oncogene tyrosine-protein kinase Src|Src]]. Loss of PLEKHA7 disrupts [[miRNA]]s regulation, causing [[tumorigenic]] signaling and growth. Restoring normal miRNA levels in tumor cells can reverse that aberrant signaling.<ref name="nature"/><ref>{{cite web |url=http://newsnetwork.mayoclinic.org/discussion/mayo-clinic-researchers-find-new-code-that-makes-reprogramming-of-cancer-cells-possible/ |title=Mayo Clinic researchers find new code that makes reprogramming of cancer cells possible|date=24 August 2015 }}</ref><ref>[http://www.nature.com/ncb/journal/vaop/ncurrent/full/ncb3227.html Distinct E-cadherin-based complexes regulate cell behaviour through miRNA processing or Src and p120 catenin activity. Kourtidis et al. 2015]</ref> In 2015 it was also discovered that PLEKHA7 has a role in controlling susceptibility to Staphylococcus aureus alpha-toxin <ref name="Popov">{{cite journal | vauthors = Popov LM, Marceau CD, Starkl PM, Lumb JH, Shah J, Guerrera D, Cooper RL, Merakou C, Bouley DM, Meng W, Kiyonari H, Takeichi M, Galli SJ, Bagnoli F, Citi S, Carette JE, Amieva MR | title = The adherens junctions control susceptibility to Staphylococcus aureus α-toxin | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 112 | issue = 46 | pages = 14337–42 | date = November 2015 | pmid = 26489655 | pmc = 4655540 | doi = 10.1073/pnas.1510265112 | bibcode = 2015PNAS..11214337P | doi-access = free }}</ref> Cells lacking PLEKHA7 are injured by the toxin, but recover after intoxication. Mice knockout for PLEKHA7 are viable and fertile, and when infected with methycillin-resistant S. aureus USA300 LAC strain they show a decreased disease severity in both skin infection and lethal pneumonia, thus identifying PLEKHA7 as a potential nonessential host target to reduce S. aureus virulence during epithelial infections.<ref name="Popov"/>

In 2016, researchers found that PLEKHA7 recruits the small PDZ protein [[PDZD11]] to adherens junctions, thus resulting in the stabilisation of [[nectins]] at adherens junctions.<ref name="jbc.org">http://www.jbc.org/content/early/2016/04/04/jbc.M115.712935.full.pdf {{Dead link|date=February 2022}}</ref> Knock-out of PLEKHA7 results in the loss of PDZD11 from epithelial adherens junctions, and this is rescued by the introduction of exogenous PLEKHA7.<ref name="jbc.org"/> The N-terminal 44 residues of PDZD11 interact with the first WW domain of PLEKHA7.<ref name="jbc.org"/> In the absence of either PLEKHA7 or PDZD11, the amount of nectin-3 and nectin-4 detected at junctions is decreased, as well as total nectin levels, through proteasome-mediated degradation.<ref name="jbc.org"/> PDZD11 interacts directly with the cytoplasmic PDZ-binding motif of nectins, through its own PDZ domain.<ref name="jbc.org"/> [[Proximity ligation assay]] shows that PLEKHA7 is associated to nectins in a PDZD11-dependent manner.<ref name="jbc.org"/> Nectins are the second major class of transmembrane adhesion molecules at adherens junctions, besides cadherins. Therefore, PLEKHA7 stabilises both cadherins and nectins at AJ.<ref name="jbc.org"/>


== Clinical significance ==
== Clinical significance ==


[[Genome-wide association studies]] suggest that PLEKHA7 is associated with [[blood pressure]] and hypertension<ref name=" pmid20414254">
[[Genome-wide association studies]] suggest that PLEKHA7 is associated with [[blood pressure]] and hypertension<ref name=" pmid20414254">
{{cite journal | vauthors = Hong KW, Jin HS, Lim JE, Kim S, Go MJ, Oh B | title = Recapitulation of two genomewide association studies on blood pressure and essential hypertension in the Korean population | journal = Journal of Human Genetics | volume = 55 | issue = 6 | pages = 336–41 | date = June 2010 | pmid = 20414254 | doi = 10.1038/jhg.2010.31 | doi-access = free }}</ref>
{{cite journal
| title=Recapitulation of two genomewide association studies on blood pressure and essential hypertension in the Korean population.
| author=Hong KW, Jin HS, Lim JE, Kim S, Go MJ, Oh B.
| journal=J Hum Genet. |date=Jun 2010
| volume=55
| issue=6
| pages=336-41.
| doi=10.1038/jhg.2010.31
| PMID=20414254
}}</ref>
<ref name="pmid22071413">
<ref name="pmid22071413">
{{cite journal | vauthors = Hotta K, Kitamoto A, Kitamoto T, Mizusawa S, Teranishi H, Matsuo T, Nakata Y, Hyogo H, Ochi H, Nakamura T, Kamohara S, Miyatake N, Kotani K, Komatsu R, Itoh N, Mineo I, Wada J, Yoneda M, Nakajima A, Funahashi T, Miyazaki S, Tokunaga K, Masuzaki H, Ueno T, Chayama K, Hamaguchi K, Yamada K, Hanafusa T, Oikawa S, Yoshimatsu H, Sakata T, Tanaka K, Matsuzawa Y, Nakao K, Sekine A | title = Genetic variations in the CYP17A1 and NT5C2 genes are associated with a reduction in visceral and subcutaneous fat areas in Japanese women | journal = Journal of Human Genetics | volume = 57 | issue = 1 | pages = 46–51 | date = January 2012 | pmid = 22071413 | doi = 10.1038/jhg.2011.127 | doi-access = free | hdl = 2433/189865 | hdl-access = free }}</ref>
{{cite journal
| title=Genetic variations in the CYP17A1 and NT5C2 genes are associated with a reduction in visceral and subcutaneous fat areas in Japanese women.
| author=Hotta| journal=J Hum Genet.
|date=Jan 2012
| volume=57
| issue=1
| pages=46-51
| doi=10.1038/jhg.2011.127
| PMID=22071413
|display-authors=etal}}</ref>
<ref name="pmid19430429">
<ref name="pmid19430429">
{{cite journal | vauthors = Levy D, Ehret GB, Rice K, Verwoert GC, Launer LJ, Dehghan A, Glazer NL, Morrison AC, Johnson AD, Aspelund T, Aulchenko Y, Lumley T, Köttgen A, Vasan RS, Rivadeneira F, Eiriksdottir G, Guo X, Arking DE, Mitchell GF, Mattace-Raso FU, Smith AV, Taylor K, Scharpf RB, Hwang SJ, Sijbrands EJ, Bis J, Harris TB, Ganesh SK, O'Donnell CJ, Hofman A, Rotter JI, Coresh J, Benjamin EJ, Uitterlinden AG, Heiss G, Fox CS, Witteman JC, Boerwinkle E, Wang TJ, Gudnason V, Larson MG, Chakravarti A, Psaty BM, van Duijn CM | title = Genome-wide association study of blood pressure and hypertension | journal = Nature Genetics | volume = 41 | issue = 6 | pages = 677–87 | date = June 2009 | pmid = 19430479 | pmc = 2998712 | doi = 10.1038/ng.384 }}</ref>
{{cite journal
| title=Genome-wide association study of blood pressure and hypertension.
| author=Levy| journal=Nat. Genet.
|date=Jun 2009
| volume=41
| issue=6
| pages=677-87
| doi=10.1038/ng.384
| PMID=19430429
|display-authors=etal}}</ref>
<ref name="pmid21963141">
<ref name="pmid21963141">
{{cite journal | vauthors = Lin Y, Lai X, Chen B, Xu Y, Huang B, Chen Z, Zhu S, Yao J, Jiang Q, Huang H, Wen J, Chen G | title = Genetic variations in CYP17A1, CACNB2 and PLEKHA7 are associated with blood pressure and/or hypertension in She ethnic minority of China | journal = Atherosclerosis | volume = 219 | issue = 2 | pages = 709–14 | date = December 2011 | pmid = 21963141 | doi = 10.1016/j.atherosclerosis.2011.09.006 }}</ref> and primary angle closure [[glaucoma]].<ref name="pmid23840785">
{{cite journal
{{cite journal | vauthors = Awadalla MS, Thapa SS, Hewitt AW, Burdon KP, Craig JE | title = Association of genetic variants with primary angle closure glaucoma in two different populations | journal = PLOS ONE | volume = 8 | issue = 6 | pages = e67903 | date = Jun 2013 | pmid = 23840785 | pmc = 3695871 | doi = 10.1371/journal.pone.0067903 | bibcode = 2013PLoSO...867903A | doi-access = free }}</ref>
| title=Genetic variations in CYP17A1, CACNB2 and PLEKHA7 are associated with blood pressure and/or hypertension in She ethnic minority of China.
| author=Lin Y, Lai X, Chen B, Xu Y, Huang B, Chen Z, Zhu S, Yao J, Jiang Q, Huang H, Wen J, Chen G.
| journal=Atherosclerosis.
|date=Dec 2011
| volume=219
| issue=2
| pages=709-14.
| doi=10.1016/j.atherosclerosis.2011.09.006
| PMID=21963141
}}</ref> and primary angle closure [[glaucoma]].<ref name="pmid23840785">
{{cite journal
| title=Association of genetic variants with primary angle closure glaucoma in two different populations.
| author=Awadalla MS, Thapa SS, Hewitt AW, Burdon KP, Craig JE.
| journal=PLoS ONE
|date=Jun 2013
| volume=8
| issue=6
| pages=e67903
| doi=10.1371/journal.pone.0067903
| PMID=23840785
| pmc=3695871
}}</ref>
<ref name="pmid23505305">
<ref name="pmid23505305">
{{cite journal | vauthors = Day AC, Luben R, Khawaja AP, Low S, Hayat S, Dalzell N, Wareham NJ, Khaw KT, Foster PJ | title = Genotype-phenotype analysis of SNPs associated with primary angle closure glaucoma (rs1015213, rs3753841 and rs11024102) and ocular biometry in the EPIC-Norfolk Eye Study | journal = The British Journal of Ophthalmology | volume = 97 | issue = 6 | pages = 704–7 | date = June 2013 | pmid = 23505305 | pmc = 4624259 | doi = 10.1136/bjophthalmol-2012-302969 }}</ref>
{{cite journal
| title=Genotype-phenotype analysis of SNPs associated with primary angle closure glaucoma (rs1015213, rs3753841 and rs11024102) and ocular biometry in the EPIC-Norfolk Eye Study.
| author=Day AC, Luben R, Khawaja AP, Low S, Hayat S, Dalzell N, Wareham NJ, Khaw KT, Foster PJ.
| journal=Br J Ophthalmol.
|date=Jun 2013
| volume=97
| issue=6
| pages=704-7
| doi=10.1136/bjophthalmol-2012-302969
| PMID=23505305
}}</ref>
<ref name="pmid23847314">
<ref name="pmid23847314">
{{cite journal | vauthors = Duvesh R, Verma A, Venkatesh R, Kavitha S, Ramulu PY, Wojciechowski R, Sundaresan P | title = Association study in a South Indian population supports rs1015213 as a risk factor for primary angle closure | journal = Investigative Ophthalmology & Visual Science | volume = 54 | issue = 8 | pages = 5624–8 | date = August 2013 | pmid = 23847314 | pmc = 3747718 | doi = 10.1167/iovs.13-12186 }}</ref>
{{cite journal
| title=Association study in a South Indian population supports rs1015213 as a risk factor for primary angle closure.
| author=Duvesh R, Verma A, Venkatesh R, Kavitha S, Ramulu PY, Wojciechowski R, Sundaresan P.
| journal=Invest Ophthalmol Vis Sci.
|date=Aug 2013
| volume=54
| issue=8
| pages=5624-8
| doi=10.1167/iovs.13-12186
| PMID=23847314
| pmc=3747718
}}</ref>
<ref name="pmid23920366">
<ref name="pmid23920366">
{{cite journal | vauthors = Nongpiur ME, Wei X, Xu L, Perera SA, Wu RY, Zheng Y, Li Y, Wang YX, Cheng CY, Jonas JB, Wong TY, Vithana EN, Aung T, Khor CC | title = Lack of association between primary angle-closure glaucoma susceptibility loci and the ocular biometric parameters anterior chamber depth and axial length | journal = Investigative Ophthalmology & Visual Science | volume = 54 | issue = 8 | pages = 5824–8 | date = August 2013 | pmid = 23920366 | doi = 10.1167/iovs.13-11901 | doi-access = free }}</ref>
{{cite journal
| title=Lack of association between primary angle-closure glaucoma susceptibility loci and the ocular biometric parameters anterior chamber depth and axial length.
| author=Nongpiur ME, Wei X, Xu L, Perera SA, Wu RY, Zheng Y, Li Y, Wang YX, Cheng CY, Jonas JB, Wong TY, Vithana EN, Aung T, Khor CC
| journal=Invest Ophthalmol Vis Sci
|date=Aug 2013
| volume=54
| issue=8
| pages=5824-8
| doi=10.1167/iovs.13-11901
| PMID=23920366
}}</ref>
<ref name="pmid24474268">
<ref name="pmid24474268">
{{cite journal | vauthors = Wei X, Nongpiur ME, de Leon MS, Baskaran M, Perera SA, How AC, Vithana EN, Khor CC, Aung T | title = Genotype-phenotype correlation analysis for three primary angle closure glaucoma-associated genetic polymorphisms | journal = Investigative Ophthalmology & Visual Science | volume = 55 | issue = 2 | pages = 1143–8 | date = February 2014 | pmid = 24474268 | doi = 10.1167/iovs.13-13552 | doi-access = }}</ref>
{{cite journal
| title=Genotype-Phenotype Correlation Analysis for Three Primary Angle Closure Glaucoma Associated Genetic Polymorphisms.
| author=Wei X, Nongpiur ME, De Leon JM, Baskaran M, Perera SA, How AC, Vithana EN, Khor CC, Aung T.
| journal=Invest Ophthalmol Vis Sci
|date=Jan 2014
| volume=55
| issue=2
| pages=1143-8
| doi=10.1167/iovs.13-13552
| PMID=24474268
}}</ref>
<ref name="pmid22922875">
<ref name="pmid22922875">
{{cite journal | vauthors = Vithana EN, Khor CC, Qiao C, Nongpiur ME, George R, Chen LJ, Do T, Abu-Amero K, Huang CK, Low S, Tajudin LA, Perera SA, Cheng CY, Xu L, Jia H, Ho CL, Sim KS, Wu RY, Tham CC, Chew PT, Su DH, Oen FT, Sarangapani S, Soumittra N, Osman EA, Wong HT, Tang G, Fan S, Meng H, Huong DT, Wang H, Feng B, Baskaran M, Shantha B, Ramprasad VL, Kumaramanickavel G, Iyengar SK, How AC, Lee KY, Sivakumaran TA, Yong VH, Ting SM, Li Y, Wang YX, Tay WT, Sim X, Lavanya R, Cornes BK, Zheng YF, Wong TT, Loon SC, Yong VK, Waseem N, Yaakub A, Chia KS, Allingham RR, Hauser MA, Lam DS, Hibberd ML, Bhattacharya SS, Zhang M, Teo YY, Tan DT, Jonas JB, Tai ES, Saw SM, Hon DN, Al-Obeidan SA, Liu J, Chau TN, Simmons CP, Bei JX, Zeng YX, Foster PJ, Vijaya L, Wong TY, Pang CP, Wang N, Aung T | title = Genome-wide association analyses identify three new susceptibility loci for primary angle closure glaucoma | journal = Nature Genetics | volume = 44 | issue = 10 | pages = 1142–1146 | date = October 2012 | pmid = 22922875 | pmc = 4333205 | doi = 10.1038/ng.2390 }}</ref>
{{cite journal
| title=Genome-wide association analyses identify three new susceptibility loci for primary angle closure glaucoma.
| author=Vithana| journal=Nat. Genet.
|date=Oct 2012
| volume=44
| issue=10
| pages=1142-6
| doi=10.1038/ng.2390
| PMID=22922875
|display-authors=etal}}</ref>
<ref name="pmid24282630">
<ref name="pmid24282630">
{{cite journal | vauthors = Shi H, Zhu R, Hu N, Shi J, Zhang J, Jiang L, Jiang H, Guan H | title = An extensive replication study on three new susceptibility Loci of primary angle closure glaucoma in han chinese: jiangsu eye study | journal = Journal of Ophthalmology | volume = 2013 | pages = 641596 | date = Jan 2013 | pmid = 24282630 | pmc = 3824414 | doi = 10.1155/2013/641596 | doi-access = free }}</ref> Also, an increased expression of PLEKHA7 in invasive lobular [[breast cancer]] has been reported.<ref name="pmid22542108">
{{cite journal
{{cite journal | vauthors = Castellana B, Escuin D, Pérez-Olabarria M, Vázquez T, Muñoz J, Peiró G, Barnadas A, Lerma E | title = Genetic up-regulation and overexpression of PLEKHA7 differentiates invasive lobular carcinomas from invasive ductal carcinomas | journal = Human Pathology | volume = 43 | issue = 11 | pages = 1902–9 | date = November 2012 | pmid = 22542108 | doi = 10.1016/j.humpath.2012.01.017 }}</ref> In a more recent study, the expression of PLEKHA7 protein in high grade ductal breast carcinomas, and lobular breast carcinomas was found to be very low or undetectable by immunofluorescence or immunohistochemistry, despite the detection of PLEKHA7 mRNA <ref>{{cite journal | vauthors = Tille JC, Ho L, Shah J, Seyde O, McKee TA, Citi S | title = The Expression of the Zonula Adhaerens Protein PLEKHA7 Is Strongly Decreased in High Grade Ductal and Lobular Breast Carcinomas | journal = PLOS ONE | volume = 10 | issue = 8 | pages = e0135442 | date = 2015-01-01 | pmid = 26270346 | pmc = 4535953 | doi = 10.1371/journal.pone.0135442 | bibcode = 2015PLoSO..1035442T | doi-access = free }}</ref> A Mayo Clinic study published online in August 2015 found that PLEKHA7 is mis-localized or lost in almost all breast and kidney tumor patient samples examined.<ref name="nature">
| title=An extensive replication study on three new susceptibility Loci of primary angle closure glaucoma in han Chinese: jiangsu eye study.
{{cite journal | vauthors = Kourtidis A, Ngok SP, Pulimeno P, Feathers RW, Carpio LR, Baker TR, Carr JM, Yan IK, Borges S, Perez EA, Storz P, Copland JA, Patel T, Thompson EA, Citi S, Anastasiadis PZ | title = Distinct E-cadherin-based complexes regulate cell behaviour through miRNA processing or Src and p120 catenin activity | journal = Nature Cell Biology | volume = 17 | issue = 9 | pages = 1145–57 | date = September 2015 | pmid = 26302406 | pmc = 4975377 | doi = 10.1038/ncb3227}}</ref>
| author=Shi H, Zhu R, Hu N, Shi J, Zhang J, Jiang L, Jiang H, Guan H.
| journal=J Ophthalmol.
|date=Jan 2013
| volume=641596
| doi=10.1155/2013/641596
| PMID=24282630
| pmc=3824414
| pages=641596
}}</ref> Also, an increased expression of PLEKHA7 in invasive lobular [[breast cancer]] has been reported.<ref name="pmid22542108">
{{cite journal
| title=Genetic up-regulation and overexpression of PLEKHA7 differentiates invasive lobular carcinomas from invasive ductal carcinomas.
| author=Castellana B, Escuin D, Pérez-Olabarria M, Vázquez T, Muñoz J, Peiró G, Barnadas A, Lerma E.
| journal=Hum Pathol.
|date=Nov 2012
| volume=43
| issue=11
| pages=1902-9
| doi=10.1016/j.humpath.2012.01.017
| PMID=22542108
}}</ref> In a more recent study, the expression of PLEKHA7 protein in high grade ductal breast carcinomas, and lobular breast carcinomas was found to be very low or undetectable by immunofluorescence or immunohistochemistry, despite the detection of PLEKHA7 mRNA <ref>{{Cite journal|title = The Expression of the Zonula Adhaerens Protein PLEKHA7 Is Strongly Decreased in High Grade Ductal and Lobular Breast Carcinomas|url = http://www.ncbi.nlm.nih.gov/pubmed/26270346|journal = PloS One|date = 2015-01-01|issn = 1932-6203|pmc = 4535953|pmid = 26270346|pages = e0135442|volume = 10|issue = 8|doi = 10.1371/journal.pone.0135442|first = Jean-Christophe|last = Tille|first2 = Liza|last2 = Ho|first3 = Jimit|last3 = Shah|first4 = Olivia|last4 = Seyde|first5 = Thomas A.|last5 = McKee|first6 = Sandra|last6 = Citi}}</ref>[http://www.ncbi.nlm.nih.gov/pubmed/26270346 .] A Mayo Clinic study published online in August 2015 found that PLEKHA7 is mis-localized or lost in almost all breast and kidney tumor patient samples examined.<ref name="nature">
{{cite journal
| title=Distinct E-cadherin-based complexes regulate cell behaviour through miRNA processing or Src and p120 catenin activity
| author=Antonis Kourtidis,
Siu P. Ngok,
Pamela Pulimeno,
Ryan W. Feathers,
Lomeli R. Carpio,
Tiffany R. Baker,
Jennifer M. Carr,
Irene K. Yan,
Sahra Borges,
Edith A. Perez,
Peter Storz,
John A. Copland,
Tushar Patel,
E. Aubrey Thompson,
Sandra Citi,
Panos Z. Anastasiadis
| journal= Nature Cell Biology
| date=24 August 2015
| volume=17
| pages=1145–1157
| doi=10.1038/ncb3227
}}</ref>


== References ==
== References ==


{{reflist|2}}
{{reflist|2}}{{Cytoskeletal proteins}}



[[Category:Cell adhesion proteins]]
[[Category:Cell adhesion proteins]]
[[Category:Transmembrane proteins]]
[[Category:Transmembrane proteins]]

Latest revision as of 05:31, 6 January 2024

PLEKHA7
Identifiers
AliasesPLEKHA7, pleckstrin homology domain containing A7
External IDsOMIM: 612686; MGI: 2445094; HomoloGene: 52172; GeneCards: PLEKHA7; OMA:PLEKHA7 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

144100

233765

Ensembl

ENSG00000166689

ENSMUSG00000045659

UniProt

Q6IQ23

Q3UIL6

RefSeq (mRNA)

NM_001329630
NM_001329631
NM_175058

NM_172743
NM_001305185
NM_001305186
NM_001305189
NM_001305190

RefSeq (protein)

NP_001316559
NP_001316560
NP_778228

Location (UCSC)Chr 11: 16.78 – 17.01 MbChr 7: 115.72 – 115.91 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

PLEKHA7 (Pleckstrin homology domain-containing family A member 7) is an adherens junction (AJ) protein, involved in the junction's integrity and stability.

History

[edit]

The protein was discovered in Masatoshi Takeichi’s lab while looking for potential binding partners for the N-terminal region of p120. PLEKHA7 was identified by mass spectrometry in lysates of human intestinal carcinoma (Caco-2) cells in a GST-pull down using N-terminal GST-fusion p120 catenin as bait.[5] It was also independently discovered in Sandra Citi’s group as a protein interacting with globular head domain of the Paracingulin in a yeast two-hybrid screen. PLEKHA7 localizes at epithelial zonular AJs.[6]

Structure

[edit]

The structure of PLEKHA7 is characterized by two WW domains followed by a Pleckstrin homology domain (PH) in the N-terminal region. In the C-terminal half, the protein contains three coiled coil (CC) domains and two Proline-rich (Pro) domains.[6] PLEKHA7 has been detected in different isoforms in a tissue specific manner. Two isoforms of 135 kDa and 145 kDa have been reported in colon, liver, lung, eye, pancreas, kidney and heart. Additionally, two major transcripts of 5.5 kb and 6.5 kb have been identified in brain, kidney, liver, small intestine, placenta and lung, while only one PLEKHA7 mRNA transcript of 5.5 kb is identified in heart, brain, colon and skeletal muscle.[6]

Protein-protein interactions

[edit]

In vitro interaction studies were pursued to map the interaction(s) of PLEKHA7 with p120 (residues 538-696), Nezha (CAMSAP3) (residues 680-821), paracingulin (residues 620-769) and Afadin (residues 120-374).[7] The protein PDZD11 was identified as a protein interacting through its N-terminal region with the N-terminal WW domain of PLEKHA7, based on 2-hybrid screen and analysis of PLEKHA7 immunoprecipitates[8] Unlike most other AJ proteins, but similar to afadin, PLEKHA7 is exclusively detected in the zonular apical part of AJ, but not in the “puncta adherentia” along lateral membranes of the epithelial cells.[6] Cellular localization and tissue distribution of PLEKHA7 has been confirmed by Immunoelectron microscopy (Immuno-EM) of wild type and knock down intestinal epithelial tissues.[6]

Function

[edit]

The first identified function of PLEKHA7 was is to contribute to integrity and stability of the zonula adherens junctions by linking the E-cadherin/p120 complex to the minus ends of microtubules (MTs) through Nezha (CAMSAP3).[5] The PLEKHA7-Nezha- MTs complex allows transport of the KIFC3 (a minus end directed motor) to the AJ. However, in Eph4 cell line, PLEKHA7 is recruited to E-cadherin based AJ by Afadin, independently of p120.[7] PLEKHA7 knockdown studies in Madin-Darby canine kidney (MDCK) cells indicated its requirement for the AJ localization of paracingulin.[9] Furthermore, the PLEKHA7 homolog in zebrafish, Hadp1, is required for proper heart function and morphogenesis in embryo, regulating the intracellular Ca2+
 dynamics through the phosphatidylinositol 4-kinase (PIK4) pathway.[10]

In 2015, researchers discovered that PLEKHA7 recruits the so-called microprocessor complex (association of Drosha and DGCR8 proteins) to a growth-inhibiting site (apical zonula adherens) in epithelial cells instead of sites at basolateral areas of cell–cell contact containing tyrosine-phosphorylated p120 and active Src. Loss of PLEKHA7 disrupts miRNAs regulation, causing tumorigenic signaling and growth. Restoring normal miRNA levels in tumor cells can reverse that aberrant signaling.[11][12][13] In 2015 it was also discovered that PLEKHA7 has a role in controlling susceptibility to Staphylococcus aureus alpha-toxin [14] Cells lacking PLEKHA7 are injured by the toxin, but recover after intoxication. Mice knockout for PLEKHA7 are viable and fertile, and when infected with methycillin-resistant S. aureus USA300 LAC strain they show a decreased disease severity in both skin infection and lethal pneumonia, thus identifying PLEKHA7 as a potential nonessential host target to reduce S. aureus virulence during epithelial infections.[14]

In 2016, researchers found that PLEKHA7 recruits the small PDZ protein PDZD11 to adherens junctions, thus resulting in the stabilisation of nectins at adherens junctions.[15] Knock-out of PLEKHA7 results in the loss of PDZD11 from epithelial adherens junctions, and this is rescued by the introduction of exogenous PLEKHA7.[15] The N-terminal 44 residues of PDZD11 interact with the first WW domain of PLEKHA7.[15] In the absence of either PLEKHA7 or PDZD11, the amount of nectin-3 and nectin-4 detected at junctions is decreased, as well as total nectin levels, through proteasome-mediated degradation.[15] PDZD11 interacts directly with the cytoplasmic PDZ-binding motif of nectins, through its own PDZ domain.[15] Proximity ligation assay shows that PLEKHA7 is associated to nectins in a PDZD11-dependent manner.[15] Nectins are the second major class of transmembrane adhesion molecules at adherens junctions, besides cadherins. Therefore, PLEKHA7 stabilises both cadherins and nectins at AJ.[15]

Clinical significance

[edit]

Genome-wide association studies suggest that PLEKHA7 is associated with blood pressure and hypertension[16] [17] [18] [19] and primary angle closure glaucoma.[20] [21] [22] [23] [24] [25] [26] Also, an increased expression of PLEKHA7 in invasive lobular breast cancer has been reported.[27] In a more recent study, the expression of PLEKHA7 protein in high grade ductal breast carcinomas, and lobular breast carcinomas was found to be very low or undetectable by immunofluorescence or immunohistochemistry, despite the detection of PLEKHA7 mRNA [28] A Mayo Clinic study published online in August 2015 found that PLEKHA7 is mis-localized or lost in almost all breast and kidney tumor patient samples examined.[11]

References

[edit]
  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000166689 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000045659 – 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. ^ a b Meng W, Mushika Y, Ichii T, Takeichi M (November 2008). "Anchorage of microtubule minus ends to adherens junctions regulates epithelial cell-cell contacts". Cell. 135 (5): 948–59. doi:10.1016/j.cell.2008.09.040. PMID 19041755. S2CID 14503414.
  6. ^ a b c d e Pulimeno P, Bauer C, Stutz J, Citi S (August 2010). "PLEKHA7 is an adherens junction protein with a tissue distribution and subcellular localization distinct from ZO-1 and E-cadherin". PLOS ONE. 5 (8): e12207. Bibcode:2010PLoSO...512207P. doi:10.1371/journal.pone.0012207. PMC 2924883. PMID 20808826.
  7. ^ a b Kurita S, Yamada T, Rikitsu E, Ikeda W, Takai Y (October 2013). "Binding between the junctional proteins afadin and PLEKHA7 and implication in the formation of adherens junction in epithelial cells". The Journal of Biological Chemistry. 288 (41): 29356–68. doi:10.1074/jbc.M113.453464. PMC 3795237. PMID 23990464.
  8. ^ Guerrera D, Shah J, Vasileva E, Sluysmans S, Méan I, Jond L, Poser I, Mann M, Hyman AA, Citi S (May 2016). "PLEKHA7 Recruits PDZD11 to Adherens Junctions to Stabilize Nectins". The Journal of Biological Chemistry. 291 (21): 11016–29. doi:10.1074/jbc.M115.712935. PMC 4900252. PMID 27044745.
  9. ^ Pulimeno P, Paschoud S, Citi S (May 2011). "A role for ZO-1 and PLEKHA7 in recruiting paracingulin to tight and adherens junctions of epithelial cells". The Journal of Biological Chemistry. 286 (19): 16743–50. doi:10.1074/jbc.M111.230862. PMC 3089516. PMID 21454477.
  10. ^ Wythe JD, Jurynec MJ, Urness LD, Jones CA, Sabeh MK, Werdich AA, Sato M, Yost HJ, Grunwald DJ, Macrae CA, Li DY (September 2011). "Hadp1, a newly identified pleckstrin homology domain protein, is required for cardiac contractility in zebrafish". Disease Models & Mechanisms. 4 (5): 607–21. doi:10.1242/dmm.002204. PMC 3180224. PMID 21628396.
  11. ^ a b Kourtidis A, Ngok SP, Pulimeno P, Feathers RW, Carpio LR, Baker TR, Carr JM, Yan IK, Borges S, Perez EA, Storz P, Copland JA, Patel T, Thompson EA, Citi S, Anastasiadis PZ (September 2015). "Distinct E-cadherin-based complexes regulate cell behaviour through miRNA processing or Src and p120 catenin activity". Nature Cell Biology. 17 (9): 1145–57. doi:10.1038/ncb3227. PMC 4975377. PMID 26302406.
  12. ^ "Mayo Clinic researchers find new code that makes reprogramming of cancer cells possible". 24 August 2015.
  13. ^ Distinct E-cadherin-based complexes regulate cell behaviour through miRNA processing or Src and p120 catenin activity. Kourtidis et al. 2015
  14. ^ a b Popov LM, Marceau CD, Starkl PM, Lumb JH, Shah J, Guerrera D, Cooper RL, Merakou C, Bouley DM, Meng W, Kiyonari H, Takeichi M, Galli SJ, Bagnoli F, Citi S, Carette JE, Amieva MR (November 2015). "The adherens junctions control susceptibility to Staphylococcus aureus α-toxin". Proceedings of the National Academy of Sciences of the United States of America. 112 (46): 14337–42. Bibcode:2015PNAS..11214337P. doi:10.1073/pnas.1510265112. PMC 4655540. PMID 26489655.
  15. ^ a b c d e f g http://www.jbc.org/content/early/2016/04/04/jbc.M115.712935.full.pdf [dead link]
  16. ^ Hong KW, Jin HS, Lim JE, Kim S, Go MJ, Oh B (June 2010). "Recapitulation of two genomewide association studies on blood pressure and essential hypertension in the Korean population". Journal of Human Genetics. 55 (6): 336–41. doi:10.1038/jhg.2010.31. PMID 20414254.
  17. ^ Hotta K, Kitamoto A, Kitamoto T, Mizusawa S, Teranishi H, Matsuo T, Nakata Y, Hyogo H, Ochi H, Nakamura T, Kamohara S, Miyatake N, Kotani K, Komatsu R, Itoh N, Mineo I, Wada J, Yoneda M, Nakajima A, Funahashi T, Miyazaki S, Tokunaga K, Masuzaki H, Ueno T, Chayama K, Hamaguchi K, Yamada K, Hanafusa T, Oikawa S, Yoshimatsu H, Sakata T, Tanaka K, Matsuzawa Y, Nakao K, Sekine A (January 2012). "Genetic variations in the CYP17A1 and NT5C2 genes are associated with a reduction in visceral and subcutaneous fat areas in Japanese women". Journal of Human Genetics. 57 (1): 46–51. doi:10.1038/jhg.2011.127. hdl:2433/189865. PMID 22071413.
  18. ^ Levy D, Ehret GB, Rice K, Verwoert GC, Launer LJ, Dehghan A, Glazer NL, Morrison AC, Johnson AD, Aspelund T, Aulchenko Y, Lumley T, Köttgen A, Vasan RS, Rivadeneira F, Eiriksdottir G, Guo X, Arking DE, Mitchell GF, Mattace-Raso FU, Smith AV, Taylor K, Scharpf RB, Hwang SJ, Sijbrands EJ, Bis J, Harris TB, Ganesh SK, O'Donnell CJ, Hofman A, Rotter JI, Coresh J, Benjamin EJ, Uitterlinden AG, Heiss G, Fox CS, Witteman JC, Boerwinkle E, Wang TJ, Gudnason V, Larson MG, Chakravarti A, Psaty BM, van Duijn CM (June 2009). "Genome-wide association study of blood pressure and hypertension". Nature Genetics. 41 (6): 677–87. doi:10.1038/ng.384. PMC 2998712. PMID 19430479.
  19. ^ Lin Y, Lai X, Chen B, Xu Y, Huang B, Chen Z, Zhu S, Yao J, Jiang Q, Huang H, Wen J, Chen G (December 2011). "Genetic variations in CYP17A1, CACNB2 and PLEKHA7 are associated with blood pressure and/or hypertension in She ethnic minority of China". Atherosclerosis. 219 (2): 709–14. doi:10.1016/j.atherosclerosis.2011.09.006. PMID 21963141.
  20. ^ Awadalla MS, Thapa SS, Hewitt AW, Burdon KP, Craig JE (Jun 2013). "Association of genetic variants with primary angle closure glaucoma in two different populations". PLOS ONE. 8 (6): e67903. Bibcode:2013PLoSO...867903A. doi:10.1371/journal.pone.0067903. PMC 3695871. PMID 23840785.
  21. ^ Day AC, Luben R, Khawaja AP, Low S, Hayat S, Dalzell N, Wareham NJ, Khaw KT, Foster PJ (June 2013). "Genotype-phenotype analysis of SNPs associated with primary angle closure glaucoma (rs1015213, rs3753841 and rs11024102) and ocular biometry in the EPIC-Norfolk Eye Study". The British Journal of Ophthalmology. 97 (6): 704–7. doi:10.1136/bjophthalmol-2012-302969. PMC 4624259. PMID 23505305.
  22. ^ Duvesh R, Verma A, Venkatesh R, Kavitha S, Ramulu PY, Wojciechowski R, Sundaresan P (August 2013). "Association study in a South Indian population supports rs1015213 as a risk factor for primary angle closure". Investigative Ophthalmology & Visual Science. 54 (8): 5624–8. doi:10.1167/iovs.13-12186. PMC 3747718. PMID 23847314.
  23. ^ Nongpiur ME, Wei X, Xu L, Perera SA, Wu RY, Zheng Y, Li Y, Wang YX, Cheng CY, Jonas JB, Wong TY, Vithana EN, Aung T, Khor CC (August 2013). "Lack of association between primary angle-closure glaucoma susceptibility loci and the ocular biometric parameters anterior chamber depth and axial length". Investigative Ophthalmology & Visual Science. 54 (8): 5824–8. doi:10.1167/iovs.13-11901. PMID 23920366.
  24. ^ Wei X, Nongpiur ME, de Leon MS, Baskaran M, Perera SA, How AC, Vithana EN, Khor CC, Aung T (February 2014). "Genotype-phenotype correlation analysis for three primary angle closure glaucoma-associated genetic polymorphisms". Investigative Ophthalmology & Visual Science. 55 (2): 1143–8. doi:10.1167/iovs.13-13552. PMID 24474268.
  25. ^ Vithana EN, Khor CC, Qiao C, Nongpiur ME, George R, Chen LJ, Do T, Abu-Amero K, Huang CK, Low S, Tajudin LA, Perera SA, Cheng CY, Xu L, Jia H, Ho CL, Sim KS, Wu RY, Tham CC, Chew PT, Su DH, Oen FT, Sarangapani S, Soumittra N, Osman EA, Wong HT, Tang G, Fan S, Meng H, Huong DT, Wang H, Feng B, Baskaran M, Shantha B, Ramprasad VL, Kumaramanickavel G, Iyengar SK, How AC, Lee KY, Sivakumaran TA, Yong VH, Ting SM, Li Y, Wang YX, Tay WT, Sim X, Lavanya R, Cornes BK, Zheng YF, Wong TT, Loon SC, Yong VK, Waseem N, Yaakub A, Chia KS, Allingham RR, Hauser MA, Lam DS, Hibberd ML, Bhattacharya SS, Zhang M, Teo YY, Tan DT, Jonas JB, Tai ES, Saw SM, Hon DN, Al-Obeidan SA, Liu J, Chau TN, Simmons CP, Bei JX, Zeng YX, Foster PJ, Vijaya L, Wong TY, Pang CP, Wang N, Aung T (October 2012). "Genome-wide association analyses identify three new susceptibility loci for primary angle closure glaucoma". Nature Genetics. 44 (10): 1142–1146. doi:10.1038/ng.2390. PMC 4333205. PMID 22922875.
  26. ^ Shi H, Zhu R, Hu N, Shi J, Zhang J, Jiang L, Jiang H, Guan H (Jan 2013). "An extensive replication study on three new susceptibility Loci of primary angle closure glaucoma in han chinese: jiangsu eye study". Journal of Ophthalmology. 2013: 641596. doi:10.1155/2013/641596. PMC 3824414. PMID 24282630.
  27. ^ Castellana B, Escuin D, Pérez-Olabarria M, Vázquez T, Muñoz J, Peiró G, Barnadas A, Lerma E (November 2012). "Genetic up-regulation and overexpression of PLEKHA7 differentiates invasive lobular carcinomas from invasive ductal carcinomas". Human Pathology. 43 (11): 1902–9. doi:10.1016/j.humpath.2012.01.017. PMID 22542108.
  28. ^ Tille JC, Ho L, Shah J, Seyde O, McKee TA, Citi S (2015-01-01). "The Expression of the Zonula Adhaerens Protein PLEKHA7 Is Strongly Decreased in High Grade Ductal and Lobular Breast Carcinomas". PLOS ONE. 10 (8): e0135442. Bibcode:2015PLoSO..1035442T. doi:10.1371/journal.pone.0135442. PMC 4535953. PMID 26270346.
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