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 residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

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

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. 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+) which stabilizes the fold. The term ''zinc finger'' was originally coined to describe the finger-like appearance of a ...

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

regulators Regulator may refer to: Technology * Regulator (automatic control), a device that maintains a designated characteristic, as in: ** Battery regulator ** Pressure regulator ** Diving regulator ** Voltage regulator * Regulator (sewer), a control de ...

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 genetics and molecular biology, a corepressor is a molecule that represses the expression of genes. In prokaryotes A prokaryote (; less commonly spelled procaryote) is a single-celled organism whose cell lacks a nucleus and other membra ...

s to modulate the activity of

GATA transcription factor The GATA transcription factor family consists of six DNA-binding proteins (GATA1-6) that regulates transcription of DNA due to their ability to bind to the DNA sequence "GATA" which can therefore affect different diseases. These six proteins a ...

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 sections of the various GATA target genes. The ZFPM2 protein interacts primarily with the

GATA4 Transcription factor GATA-4 is a protein that in humans is encoded by the ''GATA4'' gene. Function This gene encodes a member of the GATA family of zinc finger transcription factors. Members of this family recognize the GATA motif which is pr ...

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 ...

, GATA5, and GATA6 transcription factors. ZFPM2 protein's interaction with GATA4 is notable for controlling the

embryonic development In developmental biology, animal embryonic development, also known as animal embryogenesis, is the developmental stage of an animal embryo. Embryonic development starts with the fertilization of an egg cell (ovum) by a sperm, sperm cell (spermat ...

of various tissues, particularly the heart, diaphragm, and

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

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, congenital cardiovascular malformation, and congenital heart disease, is a defect in the structure of the heart or great vessels that is present at birth. A congenital h ...

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 ...

s, and

ambiguous genitalia Intersex people are those born with any of several Sexual characteristics, sex characteristics, including chromosome patterns, gonads, or sex organ, genitals that, according to the Office of the United Nations High Commissioner for Human ...

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 (biology), order Diptera, the name being derived from the Ancient Greek, Greek δι- ''di-'' "two", and πτερόν ''pteron'' "wing". Insects of this order use only a single pair of wings to fly, the hindwin ...

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 sequence i ...

. 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 striking, ...

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 Atrioventricular (having to do with an Atrium (anatomy), atrium and Ventricle (heart), ventricle) can refer to: *Left atrioventricular opening *Atrioventricular fistula *Atrioventricular node *Atrioventricular valves, the mitral valve and tricuspid ...

, 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 and sex organ 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, ...

, 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 epithelium, 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 funct ...

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

cerebellum The cerebellum (: cerebella or cerebellums; 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 it or eve ...

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

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

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

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'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...

model system. The extreme

N terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...

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

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 ...

, 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.

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, congenital cardiovascular malformation, and congenital heart disease, is a defect in the structure of the heart or great vessels that is present at birth. A congenital he ...

. 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 The truncus arteriosus is a structure that is present during embryonic development. It is an arterial trunk that originates from both ventricles of the heart that later divides into the aorta and the pulmonary trunk. Structure The truncus arteri ...

, failure to from the pulmonary artery valve combined with

ventricular septal defect A ventricular septal defect (VSD) is a defect in the ventricular septum, the wall dividing the left and right ventricles of the heart. It's a common heart problem present at birth ( congenital heart defect). The extent of the opening may vary ...

double outlet right ventricle Double outlet right ventricle (DORV) is a form of congenital heart disease where both of the great arteries connect (in whole or in part) to the right ventricle (RV). In some cases it is found that this occurs on the left side of the heart rather t ...

transposition of the great arteries Transposition of the great vessels (TGV) is a group of congenital heart defects involving an abnormal spatial arrangement of any of the great vessels: superior and/or inferior venae cavae, pulmonary artery, pulmonary veins, and aorta. Congenit ...

, and

interrupted aortic arch Interrupted aortic arch is a very rare heart defect (affecting 3 per million live births) in which the aorta is not completely developed. There is a gap between the ascending and descending thoracic aorta. In a sense it is the complete form of a coa ...

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

Hypermethylation Methylation, in the chemical sciences, is 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 terms ...

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 Protein biosynthesis, synthesizing a protein. mRNA is ...

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. Mos ...

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 microscopic ...

and pulmonary vascular disorder that leads to

pulmonary hypertension Pulmonary hypertension (PH or PHTN) is a condition of increased blood pressure in the pulmonary artery, arteries of the lungs. Symptoms include dypsnea, shortness of breath, Syncope (medicine), fainting, tiredness, chest pain, pedal edema, swell ...

. These defects are considered due to

haploinsufficiency Haploinsufficiency in genetics describes a model of dominant gene action in diploid organisms, in which a single copy of the wild-type allele at a locus in heterozygous combination with a variant allele is insufficient to produce the wild-type ...

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. Mos ...

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, variations in sex characteristics (VSC), sexual anomalies, or sexual abnormalities, are congenital conditions affecting the reproductive system, in which developme ...

. The disorder likely reflects

of the ZFPM2 protein and consequential reduced regulation of GATA4 in promoting normal development of the gonads.