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 Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

that in humans is encoded by the ''ZFPM2'' and in mice by the ''Zfpm2''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

. The

zinc finger A zinc finger is a small protein structural motif that is characterized by the coordination of one or more zinc ions (Zn2+) in order to stabilize the fold. It was originally coined to describe the finger-like appearance of a hypothesized struct ...

-containing protein encoded by this gene is a widely expressed member of the FOG family of regulators of

transcription factors In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fun ...

. 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

corepressor In the field of molecular biology, a corepressor is a molecule that represses the expression of genes. In prokaryotes, corepressors are small molecules whereas in eukaryotes, corepressors are proteins. A corepressor does not directly bind to DNA, ...

s 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. The ZFPM2 protein interacts primarily with the GATA4 but also with

GATA2 GATA2 or GATA-binding factor 2 is a transcription factor, i.e. a nuclear protein which regulates the expression of genes. It regulates many genes that are critical for the embryonic development, self-renewal, maintenance, and functionality of bl ...

, GATA5, and

GATA6 Transcription factor GATA-6, also known as GATA-binding factor 6 (GATA6), is protein that in humans is encoded by the ''GATA6'' gene. The gene product preferentially binds (A/T/C)GAT(A/T)(A) of the consensus binding sequence. Clinical signific ...

transcription factors. ZFPM2 protein's interaction with GATA4 is notable for controlling the

embryonic development An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sperm ...

of various tissues, particularly the heart, diaphragm, and

gonad A gonad, sex gland, or reproductive gland is a mixed gland that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gonad, the testicle, produces sp ...

s. Correspondingly, ''ZFPM2'' mutations are responsible for certain forms of

congenital heart defect A congenital heart defect (CHD), also known as a congenital heart anomaly and congenital heart disease, is a defect in the structure of the heart or great vessels that is present at birth. A congenital heart defect is classed as a cardiovascul ...

congenital diaphragmatic hernia Congenital diaphragmatic hernia (CDH) is a birth defect of the diaphragm. The most common type of CDH is a Bochdalek hernia; other types include Morgagni hernia, diaphragm eventration and central tendon defects of the diaphragm. Malformation of ...

s, and

ambiguous genitalia Intersex people are individuals born with any of several sex characteristics including chromosome patterns, gonads, or genitals that, according to the Office of the United Nations High Commissioner for Human Rights, "do not fit typical ...

in mice as well as humans.

Gene

The ''ZFPM2'' gene is found in a wide range of animal species from

flies Flies are insects of the order Diptera, the name being derived from the Greek δι- ''di-'' "two", and πτερόν ''pteron'' "wing". Insects of this order use only a single pair of wings to fly, the hindwings having evolved into advanced m ...

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 An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding seque ...

. The equivalent mouse gene, ''Zfpm2'', is located on chromosome 15 and consists of 8 exons.

Knockout A knockout (abbreviated to KO or K.O.) is a fight-ending, winning criterion in several full-contact combat sports, such as boxing, kickboxing, muay thai, mixed martial arts, karate, some forms of taekwondo and other sports involving strikin ...

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 Tetralogy of Fallot (TOF), formerly known as Steno-Fallot tetralogy, is a congenital heart defect characterized by four specific cardiac defects. Classically, the four defects are: *pulmonary stenosis, which is narrowing of the exit from the r ...

malformation. ''ZFPM2'' expression in mice is also required for normal development of the

gonads A gonad, sex gland, or reproductive gland is a mixed gland that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gonad, the testicle, produces sper ...

, lung and diaphragm.

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 The endometrium is the inner epithelial layer, along with its mucous membrane, of the mammalian uterus. It has a basal layer and a functional layer: the basal layer contains stem cells which regenerate the functional layer. The functional layer ...

while the mouse protein is expressed at relatively high levels in the central nervous system

cerebellum The cerebellum (Latin for "little brain") is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as or even larger. In humans, the cerebe ...

and, during the early stages of its development, the heart. Human ZFPM2 contains 8

structural motif In a chain-like biological molecule, such as a protein or nucleic acid, a structural motif is a common three-dimensional structure that appears in a variety of different, evolutionarily unrelated molecules. A structural motif does not have t ...

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 In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...

to inhibit its ability to stimulate the expression of a target gene in an

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology a ...

model system. The extreme N terminal end of the ZFPM2 protein contains two domains, one of which interacts directly with the

Mi-2/NuRD complex In the field of molecular biology, the Mi-2/NuRD (Nucleosome Remodeling Deacetylase) complex, is a group of associated proteins with both ATP-dependent chromatin remodeling and histone deacetylase activities. , Mi-2/NuRD was the only known protei ...

(i.e. nucleosome remodeling and histone deacetylase complex or NuRD complex) and other of which binds

CTBP1 C-terminal-binding protein 1 also known as CtBP1 is a protein that in humans is encoded by the ''CTBP1'' gene. CtBP1 is one of two CtBP proteins, the other protein being CtBP2. Function The CtBP1 protein was originally identified as a human prot ...

or CTBP2 proteins. The NuRD complex and the CtBPs are classified as

s. that act to promote the ability of ZFPM2 to inhibit the ability of GATA proteins to stimulate the expression of their target genes.

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 GATA3 is a transcription factor that in humans is encoded by the ''GATA3'' gene. Studies in animal models and humans indicate that it controls the expression of a wide range of biologically and clinically important genes. The GATA3 transcription ...

, GATA4, GATA5, and

, 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.

Clinical relevancy

Congenital heart disease

Mutations in the ''ZFPM2'' gene are responsible for rare and sporadic cases of

congenital heart disease A congenital heart defect (CHD), also known as a congenital heart anomaly and congenital heart disease, is a defect in the structure of the heart or great vessels that is present at birth. A congenital heart defect is classed as a cardiovascular ...

. These include cases of

Tetralogy of Fallot Tetralogy of Fallot (TOF), formerly known as Steno-Fallot tetralogy, is a congenital heart defect characterized by four specific cardiac defects. Classically, the four defects are: *pulmonary stenosis, which is narrowing of the exit from the r ...

, 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 In digital computers, an interrupt (sometimes referred to as a trap) is a request for the processor to ''interrupt'' currently executing code (when permitted), so that the event can be processed in a timely manner. If the request is accepted, ...

. Sporadic cases of Tetralogy of Fallot were also found in cases where the levels of

Hypermethylation In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These t ...

CpG site The CpG sites or CG sites are regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide in the linear sequence of bases along its 5' → 3' direction. CpG sites occur with high frequency in genomic regions called CpG isl ...

s in the ''ZFPM2'' gene promoter were greatly elevated; these cases were associated with decreases cardiac tissue levels of

mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the ...

for ''ZFPM2''. These cases likely reflect the role of ZFPM2 in promoting GATA4's function in the embryonic development of the heart.

Congenital diaphragmatic hernia

''ZFPM2''

heterozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. ...

gene mutations are responsible for sporadic cases of

s. This development disorder may be the underlying cause for the development of congenital lung

dysplasia Dysplasia is any of various types of abnormal growth or development of cells (microscopic scale) or organs ( macroscopic scale), and the abnormal histology or anatomical structure(s) resulting from such growth. Dysplasias on a mainly microscopi ...

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.

Sex development

Heterozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. ...

mutations in the ''ZFPM2'' gene are responsible for sporadic, very rare cases of a familial form of

disorders of sex development Disorders of sex development (DSDs), also known as differences in sex development, diverse sex development and variations in sex characteristics (VSC), are congenital conditions affecting the reproductive system, in which development of chromoso ...

. The disorder likely reflects haploinsufficiency of the ZFPM2 protein and consequential reduced regulation of GATA4 in promoting normal development of the gonads.