ZFPM2: Difference between revisions

Jump to navigation Jump to search
VisualWikitext
m (Bot: HTTP→HTTPS)
m (sporatic → sporadic)
Line 1: Line 1:
{{Use dmy dates|date=April 2013}}
{{Use dmy dates|date=April 2013}}
{{Infobox_gene}}
{{Infobox_gene}}
'''Zinc finger protein ZFPM2''' is a [[protein]] that in humans is encoded by the ''ZFPM2'' [[gene]].<ref name="pmid9927675">{{cite journal |vauthors=Svensson EC, Tufts RL, Polk CE, Leiden JM | title = Molecular cloning of FOG-2: a modulator of transcription factor GATA-4 in cardiomyocytes | journal = Proc Natl Acad Sci U S A | volume = 96 | issue = 3 | pages = 956–61 |date=Mar 1999 | pmid = 9927675 | pmc = 15332 | doi =10.1073/pnas.96.3.956  }}</ref><ref name="pmid10438528">{{cite journal |vauthors=Holmes M, Turner J, Fox A, Chisholm O, Crossley M, Chong B | title = hFOG-2, a novel zinc finger protein, binds the co-repressor mCtBP2 and modulates GATA-mediated activation | journal = J Biol Chem | volume = 274 | issue = 33 | pages = 23491–8 |date=Sep 1999 | pmid = 10438528 | pmc = | doi =10.1074/jbc.274.33.23491  }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: ZFPM2 zinc finger protein, multitype 2| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=23414| accessdate = }}</ref>
'''Zinc finger protein ZFPM2''', i.e. '''zinc finger protein, FOG family member 2''', but also termed ''Friend of GATA2, Friend of GATA-2, FOG2'', or ''FOG-2'', is a [[protein]] that in humans is encoded by the ''ZFPM2'' and in mice by the ''Zfpm2'' [[gene]].<ref name="pmid9927675">{{cite journal |vauthors=Svensson EC, Tufts RL, Polk CE, Leiden JM | title = Molecular cloning of FOG-2: a modulator of transcription factor GATA-4 in cardiomyocytes | journal = Proc Natl Acad Sci U S A | volume = 96 | issue = 3 | pages = 956–61 |date=Mar 1999 | pmid = 9927675 | pmc = 15332 | doi =10.1073/pnas.96.3.956  }}</ref><ref name="pmid10438528">{{cite journal |vauthors=Holmes M, Turner J, Fox A, Chisholm O, Crossley M, Chong B | title = hFOG-2, a novel zinc finger protein, binds the co-repressor mCtBP2 and modulates GATA-mediated activation | journal = J Biol Chem | volume = 274 | issue = 33 | pages = 23491–8 |date=Sep 1999 | pmid = 10438528 | pmc = | doi =10.1074/jbc.274.33.23491  }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: ZFPM2 zinc finger protein, multitype 2| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=23414| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
<!-- The PBB_Summary template is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
{{PBB_Summary
{{PBB_Summary
| section_title =  
| section_title =  
| summary_text = The zinc finger protein encoded by this gene is a widely expressed member of the FOG family of transcription factors. The family members modulate the activity of GATA family proteins, which are important regulators of hematopoiesis and cardiogenesis in mammals. It has been demonstrated that the protein can both activate and down-regulate expression of GATA-target genes, suggesting different modulation in different promoter contexts. A related mRNA suggests an alternatively spliced product but this information is not yet fully supported by the sequence.<ref name="entrez" />
| summary_text = The [[zinc finger]]-containing protein encoded by this gene is a widely expressed member of the FOG family of [[Transcriptional regulation|regulators]] of [[transcription factors]]. The family consists of the ''[[ZFPM1]]'' and ''ZFPM2'' genes in humans  and ''Zfpm1'' and ''Zfpm2'' genes in mice. Its members may act as [[Coactivator (genetics)|coactivators]] and/or [[corepressor]]s to modulate the activity of [[GATA transcription factor]]s. That is, the ZFPM2 protein appears able to interact directly with and thereby either enhance or repress the ability of GATA transcription factors to stimulate the expression of their target genes; the direction of ZFPM2's actions depends on the contexts of the [[Promoter (genetics)|promoter]] sections of the various GATA target genes.<ref name="entrez" />
}}
}}


Mutations in ZFPM2 cause {{SWL|type=genetic_defect_results_in_disease|target=Congenital diaphragmatic hernia|label=Congenital Diaphragmatic Hernia}}.<ref>{{Cite journal
The ZFPM2 protein interacts primarily with the [[GATA4]] but also with [[GATA2]], [[GATA5]], and [[GATA6]] transcription factors. ZFPM2 protein's interaction with GATA4 is notable for controlling the [[embryonic development]] of various tissues, particularly the heart, diaphragm, and [[gonad]]s. Correspondingly, ''ZFPM2'' mutations are responsible for certain forms of [[congenital heart defect]]s, {{SWL|type=genetic_defect_results_in_disease|target=congenital diaphragmatic hernia|label=congenital diaphragmatic hernias}},<ref name="pmid24769157">{{cite journal | vauthors = Brady PD, Van Houdt J, Callewaert B, Deprest J, Devriendt K, Vermeesch JR | title = Exome sequencing identifies ZFPM2 as a cause of familial isolated congenital diaphragmatic hernia and possibly cardiovascular malformations | journal = European Journal of Medical Genetics | volume = 57 | issue = 6 | pages = 247–52 | date = 2014 | pmid = 24769157 | doi = 10.1016/j.ejmg.2014.04.006 | url = }}</ref> and [[ambiguous genitalia]]<ref name="pmid27899089">{{cite journal | vauthors = Brauner R, Picard-Dieval F, Lottmann H, Rouget S, Bignon-Topalovic J, Bashamboo A, McElreavey K | title = Familial forms of disorders of sex development may be common if infertility is considered a comorbidity | journal = BMC Pediatrics | volume = 16 | issue = 1 | pages = 195 | date = November 2016 | pmid = 27899089 | pmc = 5129225 | doi = 10.1186/s12887-016-0737-0 | url = }}</ref> in mice as well as humans.
| pmid = 24769157
| year = 2014
| author1 = Brady
| first1 = P
| title = Exome sequencing identifies ZFPM2 as a cause of familial isolated Congenital Diaphragmatic Hernia and possibly cardiovascular malformations
| journal = European Journal of Medical Genetics
| last2 = Van Houdt
| first2 = J
| last3 = Callewaert
| first3 = B
| last4 = Deprest
| first4 = J
| last5 = Devriendt
| first5 = K
| last6 = Vermeesch
| first6 = J. R.
| doi = 10.1016/j.ejmg.2014.04.006
| volume=57
| issue=6
| pages=247–52
}}</ref>


==Interactions==
== Gene ==
ZFPM2 has been shown to [[Protein-protein interaction|interact]] with [[GATA4]],<ref name=autogenerated1>{{cite journal |last=Svensson |first=E C |authorlink= |author2=Tufts R L |author3=Polk C E |author4=Leiden J M  |date=Feb 1999 |title=Molecular cloning of FOG-2: a modulator of transcription factor GATA-4 in cardiomyocytes |journal=[[PNAS|Proc. Natl. Acad. Sci. U.S.A.]] |volume=96 |issue=3 |pages=956–61 |publisher= |location = UNITED STATES| issn = 0027-8424| pmid = 9927675 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = |doi=10.1073/pnas.96.3.956 |pmc=15332 }}</ref> [[GATA1]]<ref name=autogenerated2>{{cite journal |last=Holmes |first=M |authorlink= |author2=Turner J |author3=Fox A |author4=Chisholm O |author5=Crossley M |author6=Chong B  |date=Aug 1999 |title=hFOG-2, a novel zinc finger protein, binds the co-repressor mCtBP2 and modulates GATA-mediated activation |journal=J. Biol. Chem. |volume=274 |issue=33 |pages=23491–8 |publisher= |location = UNITED STATES| issn = 0021-9258| pmid = 10438528 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = |doi=10.1074/jbc.274.33.23491 }}</ref> and [[CTBP2]].<ref name=pmid10438528/>
The ''ZFPM2'' gene is found in a wide range of animal species from [[fly|flies]] to humans. The human gene is located on the long or "q" arm of chromosome 8 at position 23.1 (i.e. 8q23.1) and consists of 9 [[exons]].<ref name="ncbi.nlm.nih.gov">https://www.ncbi.nlm.nih.gov/gene/23414</ref> The equivalent mouse gene, ''Zfpm2'', is located on chromosome 15 and consists of 8 exons.<ref name="ReferenceA">https://www.ncbi.nlm.nih.gov/gene/22762</ref> [[Knockout]] of ''ZFPM2'' is embryonic lethal in mice, with mice dying at embryonic day 12.5-15.5 due to congenital cardiac defects (thin [[Ventricle (heart)|heart ventricular muscle]], common [[atrioventricular canal]], and the [[tetralogy of Fallot]] malformation.<ref name="pmid15659346">{{cite journal | vauthors = Cantor AB, Orkin SH | title = Coregulation of GATA factors by the Friend of GATA (FOG) family of multitype zinc finger proteins | journal = Seminars in Cell & Developmental Biology | volume = 16 | issue = 1 | pages = 117–28 | date = February 2005 | pmid = 15659346 | doi = 10.1016/j.semcdb.2004.10.006 | url = }}</ref> ''ZFPM2'' expression in mice is also required for normal development of the [[gonads]], lung and diaphragm.<ref name="pmid23048181">{{cite journal | vauthors = Chlon TM, Crispino JD | title = Combinatorial regulation of tissue specification by GATA and FOG factors | journal = Development | volume = 139 | issue = 21 | pages = 3905–16 | date = November 2012 | pmid = 23048181 | pmc = 3472596 | doi = 10.1242/dev.080440 | url = }}</ref>
 
== Protein ==
Both the human and mouse ZFPM2 proteins consists of 1151 amino acids and are expressed in various tissues. The human protein is expressed at relatively high levels in the adult ovary and uterine [[endometrium]] while the mouse protein is expressed at relatively high levels in the central nervous system [[cerebellum]] and, during the early stages of its development, the heart. Human ZFPM2 contains 8 [[zinc finger]] [[structural motif]]s and interacts directly with various members of the [[GATA transcription factor]] family to modify their ability to stimulate the expression of their target genes. For example, it has been shown to bind directly with the N-terminal zinc finger of the [[GATA4]] [[transcription factor]] to inhibit its ability to stimulate the expression of a target gene in an  [[in vitro]] model system.<ref name="pmid23048181"/><ref name="pmid29018978">{{cite journal | vauthors = Pu T, Liu Y, Xu R, Li F, Chen S, Sun K | title = Identification of ZFPM2 mutations in sporadic conotruncal heart defect patients | journal = Molecular Genetics and Genomics : MGG | volume = 293 | issue = 1 | pages = 217–223 | date = February 2018 | pmid = 29018978 | doi = 10.1007/s00438-017-1373-6 | url = }}</ref><ref name="ReferenceA"/><ref name="ncbi.nlm.nih.gov"/>
 
The extreme [[N terminal]] end of the ZFPM2 protein contains two domains, one of which interacts directly with the [[Mi-2/NuRD complex]] (i.e. nucleosome remodeling and histone deacetylase complex or NuRD complex) and other of which binds [[CTBP1]] or [[CTBP2]] proteins. The NuRD complex and the CtBPs are classified as [[corepressor]]s. that act to promote the ability of ZFPM2 to inhibit the ability of GATA proteins to stimulate the expression of their target genes.<ref name="pmid23048181"/>
 
== Pathophysiology ==
ZFPM2 regulates the expression of certain GATA target genes by up-regulating or down-regulating the ability of the GATA transcription factors, primarily [[GATA3]], [[GATA4]], [[GATA5]], and [[GATA6]], to stimulate the expression of their target genes. Interactions with the NuRD complex or a CTBP can cause ZFPM2 to inhibit the ability of GATA3-6 proteins to stimulate the expression of their target genes.<ref name="pmid23048181"/>
 
== Clinical relevancy ==
=== Congenital heart disease ===
Mutations in the ''ZFPM2'' gene are responsible for rare and sporadic cases of [[congenital heart disease]]. These include cases of [[Tetralogy of Fallot]], [[truncus arteriosus]], [[Pulmonary atresia|failure to from the pulmonary artery valve]] combined with [[ventricular septal defect]], [[double outlet right ventricle]], [[transposition of the great arteries]], and [[interrupted aortic arch]].<ref name="pmid29018978"/> Sporadic cases of Tetralogy of Fallot were also found in cases where the levels of [[DNA methylation|Hypermethylation]] at [[CpG site]]s in the ''ZFPM2'' gene [[Promoter (genetics)|promotor]] were greatly elevated; these cases were associated with decreases cardiac tissue levels of [[mRNA]] for ''ZFPM2''.<ref name="pmid26959486">{{cite journal | vauthors = Sheng W, Chen L, Wang H, Ma X, Ma D, Huang G | title = CpG island shore methylation of ZFPM2 is identified in tetralogy of fallot samples | journal = Pediatric Research | volume = 80 | issue = 1 | pages = 151–8 | date = July 2016 | pmid = 26959486 | doi = 10.1038/pr.2016.42 | url = }}</ref> These cases likely reflect the role of ZFPM2 in promoting GATA4's function in the embryonic development of the heart.<ref name="pmid15659346"/><ref name="pmid23048181"/>
 
=== Congenital diaphragmatic hernia ===
''ZFPM2'' [[heterozygous]] gene mutations are responsible for sporadic cases of [[congenital diaphragmatic hernia]]s. This development disorder may be the underlying cause for the development of congenital lung [[dysplasia]] and pulmonary vascular disorder that leads to [[pulmonary hypertension]]. These defects are considered due to [[haploinsufficiency]] in ZFPM2 protein and consequential failure of GATA4 to promote normal lung development.<ref name="pmid24769157"/><ref name="pmid28768736">{{cite journal | vauthors = Kardon G, Ackerman KG, McCulley DJ, Shen Y, Wynn J, Shang L, Bogenschutz E, Sun X, Chung WK | title = Congenital diaphragmatic hernias: from genes to mechanisms to therapies | journal = Disease Models & Mechanisms | volume = 10 | issue = 8 | pages = 955–970 | date = August 2017 | pmid = 28768736 | pmc = 5560060 | doi = 10.1242/dmm.028365 | url = }}</ref>
 
=== Sex development ===
[[Heterozygous]] mutations in the ''ZFPM2'' gene are responsible for sporadic, very rare cases of a familial form of [[disorders of sex development]], [[ambiguous genitalia]]. The disorder likely reflects [[haploinsufficiency]] of the ZFPM2 protein and consequential reduced regulation of GATA4 in promoting normal development of the gonads.<ref name="pmid27899089"/>


==References==
==References==
Line 65: Line 62:
| update_citations = yes
| update_citations = yes
}}
}}
{{gene-8-stub}}

Revision as of 05:04, 6 July 2018

VALUE_ERROR (nil)
Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

n/a

n/a

Ensembl

n/a

n/a

UniProt

n/a

n/a

RefSeq (mRNA)

n/a

n/a

RefSeq (protein)

n/a

n/a

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

Zinc finger protein ZFPM2, i.e. zinc finger protein, FOG family member 2, but also termed Friend of GATA2, Friend of GATA-2, FOG2, or FOG-2, is a protein that in humans is encoded by the ZFPM2 and in mice by the Zfpm2 gene.[1][2][3]

The zinc finger-containing protein encoded by this gene is a widely expressed member of the FOG family of regulators of transcription factors. The family consists of the ZFPM1 and ZFPM2 genes in humans and Zfpm1 and Zfpm2 genes in mice. Its members may act as coactivators and/or corepressors to modulate the activity of GATA transcription factors. That is, the ZFPM2 protein appears able to interact directly with and thereby either enhance or repress the ability of GATA transcription factors to stimulate the expression of their target genes; the direction of ZFPM2's actions depends on the contexts of the promoter sections of the various GATA target genes.[3]

The ZFPM2 protein interacts primarily with the GATA4 but also with GATA2, GATA5, and GATA6 transcription factors. ZFPM2 protein's interaction with GATA4 is notable for controlling the embryonic development of various tissues, particularly the heart, diaphragm, and gonads. Correspondingly, ZFPM2 mutations are responsible for certain forms of congenital heart defects, congenital diaphragmatic hernias ,[4] and ambiguous genitalia[5] in mice as well as humans.

Gene

The ZFPM2 gene is found in a wide range of animal species from flies to humans. The human gene is located on the long or "q" arm of chromosome 8 at position 23.1 (i.e. 8q23.1) and consists of 9 exons.[6] The equivalent mouse gene, Zfpm2, is located on chromosome 15 and consists of 8 exons.[7] Knockout of ZFPM2 is embryonic lethal in mice, with mice dying at embryonic day 12.5-15.5 due to congenital cardiac defects (thin heart ventricular muscle, common atrioventricular canal, and the tetralogy of Fallot malformation.[8] ZFPM2 expression in mice is also required for normal development of the gonads, lung and diaphragm.[9]

Protein

Both the human and mouse ZFPM2 proteins consists of 1151 amino acids and are expressed in various tissues. The human protein is expressed at relatively high levels in the adult ovary and uterine endometrium while the mouse protein is expressed at relatively high levels in the central nervous system cerebellum and, during the early stages of its development, the heart. Human ZFPM2 contains 8 zinc finger structural motifs and interacts directly with various members of the GATA transcription factor family to modify their ability to stimulate the expression of their target genes. For example, it has been shown to bind directly with the N-terminal zinc finger of the GATA4 transcription factor to inhibit its ability to stimulate the expression of a target gene in an in vitro model system.[9][10][7][6]

The extreme N terminal end of the ZFPM2 protein contains two domains, one of which interacts directly with the Mi-2/NuRD complex (i.e. nucleosome remodeling and histone deacetylase complex or NuRD complex) and other of which binds CTBP1 or CTBP2 proteins. The NuRD complex and the CtBPs are classified as corepressors. that act to promote the ability of ZFPM2 to inhibit the ability of GATA proteins to stimulate the expression of their target genes.[9]

Pathophysiology

ZFPM2 regulates the expression of certain GATA target genes by up-regulating or down-regulating the ability of the GATA transcription factors, primarily GATA3, GATA4, GATA5, and GATA6, to stimulate the expression of their target genes. Interactions with the NuRD complex or a CTBP can cause ZFPM2 to inhibit the ability of GATA3-6 proteins to stimulate the expression of their target genes.[9]

Clinical relevancy

Congenital heart disease

Mutations in the ZFPM2 gene are responsible for rare and sporadic cases of congenital heart disease. These include cases of Tetralogy of Fallot, truncus arteriosus, failure to from the pulmonary artery valve combined with ventricular septal defect, double outlet right ventricle, transposition of the great arteries, and interrupted aortic arch.[10] Sporadic cases of Tetralogy of Fallot were also found in cases where the levels of Hypermethylation at CpG sites in the ZFPM2 gene promotor were greatly elevated; these cases were associated with decreases cardiac tissue levels of mRNA for ZFPM2.[11] These cases likely reflect the role of ZFPM2 in promoting GATA4's function in the embryonic development of the heart.[8][9]

Congenital diaphragmatic hernia

ZFPM2 heterozygous gene mutations are responsible for sporadic cases of congenital diaphragmatic hernias. This development disorder may be the underlying cause for the development of congenital lung dysplasia and pulmonary vascular disorder that leads to pulmonary hypertension. These defects are considered due to haploinsufficiency in ZFPM2 protein and consequential failure of GATA4 to promote normal lung development.[4][12]

Sex development

Heterozygous mutations in the ZFPM2 gene are responsible for sporadic, very rare cases of a familial form of disorders of sex development, ambiguous genitalia. The disorder likely reflects haploinsufficiency of the ZFPM2 protein and consequential reduced regulation of GATA4 in promoting normal development of the gonads.[5]

References

  1. ↑ Svensson EC, Tufts RL, Polk CE, Leiden JM (Mar 1999). "Molecular cloning of FOG-2: a modulator of transcription factor GATA-4 in cardiomyocytes". Proc Natl Acad Sci U S A. 96 (3): 956–61. doi:10.1073/pnas.96.3.956. PMC 15332. PMID 9927675.
  2. ↑ Holmes M, Turner J, Fox A, Chisholm O, Crossley M, Chong B (Sep 1999). "hFOG-2, a novel zinc finger protein, binds the co-repressor mCtBP2 and modulates GATA-mediated activation". J Biol Chem. 274 (33): 23491–8. doi:10.1074/jbc.274.33.23491. PMID 10438528.
  3. ↑ 3.0 3.1 "Entrez Gene: ZFPM2 zinc finger protein, multitype 2".
  4. ↑ 4.0 4.1 Brady PD, Van Houdt J, Callewaert B, Deprest J, Devriendt K, Vermeesch JR (2014). "Exome sequencing identifies ZFPM2 as a cause of familial isolated congenital diaphragmatic hernia and possibly cardiovascular malformations". European Journal of Medical Genetics. 57 (6): 247–52. doi:10.1016/j.ejmg.2014.04.006. PMID 24769157.
  5. ↑ 5.0 5.1 Brauner R, Picard-Dieval F, Lottmann H, Rouget S, Bignon-Topalovic J, Bashamboo A, McElreavey K (November 2016). "Familial forms of disorders of sex development may be common if infertility is considered a comorbidity". BMC Pediatrics. 16 (1): 195. doi:10.1186/s12887-016-0737-0. PMC 5129225. PMID 27899089.
  6. ↑ 6.0 6.1 https://www.ncbi.nlm.nih.gov/gene/23414
  7. ↑ 7.0 7.1 https://www.ncbi.nlm.nih.gov/gene/22762
  8. ↑ 8.0 8.1 Cantor AB, Orkin SH (February 2005). "Coregulation of GATA factors by the Friend of GATA (FOG) family of multitype zinc finger proteins". Seminars in Cell & Developmental Biology. 16 (1): 117–28. doi:10.1016/j.semcdb.2004.10.006. PMID 15659346.
  9. ↑ 9.0 9.1 9.2 9.3 9.4 Chlon TM, Crispino JD (November 2012). "Combinatorial regulation of tissue specification by GATA and FOG factors". Development. 139 (21): 3905–16. doi:10.1242/dev.080440. PMC 3472596. PMID 23048181.
  10. ↑ 10.0 10.1 Pu T, Liu Y, Xu R, Li F, Chen S, Sun K (February 2018). "Identification of ZFPM2 mutations in sporadic conotruncal heart defect patients". Molecular Genetics and Genomics : MGG. 293 (1): 217–223. doi:10.1007/s00438-017-1373-6. PMID 29018978.
  11. ↑ Sheng W, Chen L, Wang H, Ma X, Ma D, Huang G (July 2016). "CpG island shore methylation of ZFPM2 is identified in tetralogy of fallot samples". Pediatric Research. 80 (1): 151–8. doi:10.1038/pr.2016.42. PMID 26959486.
  12. ↑ Kardon G, Ackerman KG, McCulley DJ, Shen Y, Wynn J, Shang L, Bogenschutz E, Sun X, Chung WK (August 2017). "Congenital diaphragmatic hernias: from genes to mechanisms to therapies". Disease Models & Mechanisms. 10 (8): 955–970. doi:10.1242/dmm.028365. PMC 5560060. PMID 28768736.

Further reading


Retrieved from "https://www.wikidoc.org/index.php?title=ZFPM2&oldid=1523702"