Zinc transporter ZIP9, also known as Zrt- and Irt-like protein 9 (ZIP9) and solute carrier family 39 member 9, 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, respo ...

that in humans is encoded by the ''SLC39A9''

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 ba ...

. This protein is the 9th member out of 14 ZIP family proteins, which is a

membrane androgen receptor Membrane androgen receptors (mARs) are a group of G protein-coupled receptors (GPCRs) which bind and are activated by testosterone and/or other androgens. Unlike the androgen receptor (AR), a nuclear receptor which mediates its effects via genomi ...

(mAR)

coupled ''Coupled'' is an American dating game show that aired on Fox Broadcasting Company, Fox from May 17 to August 2, 2016. It was hosted by television personality, Terrence J and created by Mark Burnett, of ''Survivor (U.S. TV series), Survivor'', ''T ...

G protein G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their act ...

s, and also classified as a

zinc transporter protein Zinc transporter proteins (Zrt), or simply zinc transporters, are membrane transport proteins of the solute carrier family which control the membrane transport of zinc and regulate its intracellular and cytoplasmic concentrations. They include two ...

. ZIP family proteins

transport Transport (in British English), or transportation (in American English), is the intentional movement of humans, animals, and goods from one location to another. Modes of transport include air, land (rail and road), water, cable, pipeline, an ...

zinc metal from the

extracellular environment This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

into

cells Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery w ...

through

cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...

Classification and nomenclature

Mammalian cells have two major groups of

s; the ones that export zinc from the

cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...

to the

extracellular space Extracellular space refers to the part of a multicellular organism outside the cells, usually taken to be outside the plasma membranes, and occupied by fluid. This is distinguished from intracellular space, which is inside the cells. The compositi ...

( efflux), which are called ZnT (SLC30 family) , and ZIP (SLC39 family) proteins whose functions are in the opposite direction (

influx Influx may refer to: * Flux (biology) of ions, molecules or other substances from the extracellular space to the intracellular space * ''Influx'', a 2014 science-fiction novel by Daniel Suarez Daniel is a masculine given name and a surname of ...

). ZIP family proteins are named as Zrt- and Irt-like proteins because of their similarities to Zrt and Irt proteins which are respectively

zinc Zinc is a chemical element with the symbol Zn and atomic number 30. Zinc is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodi ...

and

iron Iron () is a chemical element with symbol Fe (from la, ferrum) and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, right in f ...

-regulated transporter proteins in

yeast Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are estimated to constitut ...

and

Arabidopsis ''Arabidopsis'' (rockcress) is a genus in the family Brassicaceae. They are small flowering plants related to cabbage and mustard. This genus is of great interest since it contains thale cress (''Arabidopsis thaliana''), one of the model organi ...

that were discovered earlier than ZIP and ZnT proteins. ZIP family consists of four subfamilies (I, II, LIV-1, and gufA), and ZIP9 is the only member of subfamily I.

Isoforms

ZIP9 can be present as 3 different

isoforms A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...

in human

. The canonical

isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...

of this protein has a length of 307

amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

, with a

molecular mass The molecular mass (''m'') is the mass of a given molecule: it is measured in daltons (Da or u). Different molecules of the same compound may have different molecular masses because they contain different isotopes of an element. The related quanti ...

of 32,251 Da. In the second isoform, amino acids 135-157 are missing, so its length and

molecular weight A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioch ...

are respectively reduced to 284 amino acids and 29,931 Da. In the third isoform the amino acids 233-307 are missing, so the isoform only has 232 amino acids and its molecular mass is 24,626 Da. Additionally, the last amino acid of isoform 3, which is usually

serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form un ...

, is replaced with

aspartic acid Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the pro ...

Discovery

ZIP9

was first discovered in Atlantic croaker (''Micropogonias undulatus)''

brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...

ovary The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body. ...

and

testicular A testicle or testis (plural testes) is the male reproductive gland or gonad in all bilaterians, including humans. It is homologous to the female ovary. The functions of the testes are to produce both sperm and androgens, primarily testost ...

tissues and named "AR2" in 1999, together with another

androgen receptor The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone in th ...

which was found only in brain tissue, and it was named "AR1" in that time. AR1 and AR2 were first thought to be nuclear androgen receptors (nAR), however, further studies on their biochemical and

functional Functional may refer to: * Movements in architecture: ** Functionalism (architecture) ** Form follows function * Functional group, combination of atoms within molecules * Medical conditions without currently visible organic basis: ** Functional sy ...

features in 2003 illustrated that they were involved in non-genomic mechanisms in the

plasma membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...

of the cells and were

s. In 2005, the similarities between the

nucleotide Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules wi ...

and amino acid

sequences In mathematics, a sequence is an enumerated collection of objects in which repetitions are allowed and order matters. Like a set, it contains members (also called ''elements'', or ''terms''). The number of elements (possibly infinite) is called t ...

of AR2 and ZIP family proteins were discovered in other

vertebrate Vertebrates () comprise all animal taxa within the subphylum Vertebrata () ( chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, ...

s, suggesting that AR2 is from this family of proteins. A study in 2014 utilised the latest research technologies to clone and

express Express or EXPRESS may refer to: Arts, entertainment, and media Films * '' Express: Aisle to Glory'', a 1998 comedy short film featuring Kal Penn * '' The Express: The Ernie Davis Story'', a 2008 film starring Dennis Quaid Music * ''Express'' ...

a particular

cDNA In genetics, complementary DNA (cDNA) is DNA synthesized from a single-stranded RNA (e.g., messenger RNA (mRNA) or microRNA (miRNA)) template in a reaction catalyzed by the enzyme reverse transcriptase. cDNA is often used to express a speci ...

of the female Atlantic croaker ovaries, which

encoded In communications and information processing, code is a system of rules to convert information—such as a letter, word, sound, image, or gesture—into another form, sometimes shortened or secret, for communication through a communication ...

a protein showing the characteristics of the canonical isoform of ZIP9, as a novel membrane androgen receptor(mAR). PDB 1hzx 7TM Sketch Membrane

Structure

Unlike other ZIP subfamilies that are consisted of 8 transmembrane (TM) domains with an

extracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...

, ZIP9 consists of a 7 TM structure with an

intracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

C-terminus. ZIP9 is shorter than other ZIP proteins, and only has about 307 amino acids within its structure, however, like other ZIP proteins, between its domains III and IV, within the intracellular

loop Loop or LOOP may refer to: Brands and enterprises * Loop (mobile), a Bulgarian virtual network operator and co-founder of Loop Live * Loop, clothing, a company founded by Carlos Vasquez in the 1990s and worn by Digable Planets * Loop Mobile, an ...

, it contains

histidine Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated –NH3+ form under biological conditions), a carboxylic acid group (which is in the de ...

-rich clusters. ZIP9 and other ZIP proteins have

polar Polar may refer to: Geography Polar may refer to: * Geographical pole, either of two fixed points on the surface of a rotating body or planet, at 90 degrees from the equator, based on the axis around which a body rotates * Polar climate, the c ...

or charged amino acids in their TM domains which probably play important roles in making ion transfer channels and therefore in importing zinc ions into cytoplasm.

Location, expression and function

ZIP9 influxes zinc ions into the

cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...

and its gene is expressed almost in every tissue of human body. The sub-cellular location of ZIP9 is in

plasma Plasma or plasm may refer to: Science * Plasma (physics), one of the four fundamental states of matter * Plasma (mineral), a green translucent silica mineral * Quark–gluon plasma, a state of matter in quantum chromodynamics Biology * Blood pla ...

nucleus Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom *Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucle ...

endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...

and

mitochondrial membrane A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used t ...

. One of the responsibilities of ZIP9 is the

homeostasis In biology, homeostasis (British English, British also homoeostasis) Help:IPA/English, (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physics, physical, and chemistry, chemical conditions maintained by organism, living systems. Thi ...

in th
secretory pathway
during which this protein stays within the Trans Golgi Network regardless of the change in the

concentration In chemistry, concentration is the abundance of a constituent divided by the total volume of a mixture. Several types of mathematical description can be distinguished: '' mass concentration'', ''molar concentration'', ''number concentration'', an ...

s of zinc. ZIP9 is the only ZIP protein that

signals In signal processing, a signal is a function that conveys information about a phenomenon. Any quantity that can vary over space or time can be used as a signal to share messages between observers. The ''IEEE Transactions on Signal Processing'' ...

through

binding, and pharmaceutical agents decrease its

ligand binding In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usually a mole ...

once ZIP9 is uncoupled from G proteins. ZIP9 is also the only member of ZIP family with

mAR Mar, mar or MAR may refer to: Culture * Mar or Mor, an honorific in Syriac * Earl of Mar, an earldom in Scotland * MAA (singer) (born 1986), Japanese * Marathi language, by ISO 639-2 language code * March, as an abbreviation for the third month ...

characteristics.

Ligands

Testosterone Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testes and prostate, as well as promoting secondar ...

has high

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Partn ...

for ZIP9 with a K_d of 14 nM and acts as an

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

of the receptor. In contrast, the other

endogenous Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell. In contrast, exogenous substances and processes are those that originate from outside of an organism. For example, es ...

androgen An androgen (from Greek ''andr-'', the stem of the word meaning "man") is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This inc ...

dihydrotestosterone Dihydrotestosterone (DHT, 5α-dihydrotestosterone, 5α-DHT, androstanolone or stanolone) is an endogenous androgen sex steroid and hormone. The enzyme 5α-reductase catalyzes the formation of DHT from testosterone in certain tissues includi ...

(DHT) and

androstenedione Androstenedione, or 4-androstenedione (abbreviated as A4 or Δ4-dione), also known as androst-4-ene-3,17-dione, is an endogenous weak androgen steroid hormone and intermediate in the biosynthesis of estrone and of testosterone from dehydroepia ...

show low

for the receptor with less than 1% of that of testosterone, although DHT is still effective in activating the

receptor Receptor may refer to: * Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...

at sufficiently high concentrations. Moreover, the

synthetic Synthetic things are composed of multiple parts, often with the implication that they are artificial. In particular, 'synthetic' may refer to: Science * Synthetic chemical or compound, produced by the process of chemical synthesis * Synthetic o ...

androgens

mibolerone Mibolerone, also known as dimethylnortestosterone (DMNT) and sold under the brand names Cheque Drops and Matenon, is a synthetic compound, synthetic, oral administration, orally active, and extremely potency (pharmacology), potent anabolic–andr ...

and

metribolone Metribolone (developmental code R1881, also known as methyltrienolone) is a synthetic compound, synthetic and oral administration, orally active anabolic–androgenic steroid (AAS) and a 17α-alkylated anabolic steroid, 17α-alkylated nandrolone ...

(R-1881), the endogenous androgen 11-ketotestoterone, and the other

steroid hormone A steroid hormone is a steroid that acts as a hormone. Steroid hormones can be grouped into two classes: corticosteroids (typically made in the adrenal cortex, hence ''cortico-'') and sex steroids (typically made in the gonads or placenta). Wi ...

estradiol Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is responsible for the development of f ...

and

cortisol Cortisol is a steroid hormone, in the glucocorticoid class of hormones. When used as a medication, it is known as hydrocortisone. It is produced in many animals, mainly by the ''zona fasciculata'' of the adrenal cortex in the adrenal gland ...

are all ineffective competitors for the receptor. Since mibolerone and metribolone bind to and activate the nuclear

(AR) but not ZIP9, they could potentially be employed to differentiate between AR- and ZIP9-mediated responses of testosterone. The

nonsteroidal antiandrogen A nonsteroidal antiandrogen (NSAA) is an antiandrogen with a nonsteroidal chemical structure. They are typically selective and full or silent antagonists of the androgen receptor (AR) and act by directly blocking the effects of androgens like t ...

bicalutamide Bicalutamide, sold under the brand name Casodex among others, is an antiandrogen medication that is primarily used to treat prostate cancer. It is typically used together with a gonadotropin-releasing hormone (GnRH) analogue or surgical remo ...

has been identified as an

antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...

of ZIP9.

Clinical significance

Zinc Zinc is a chemical element with the symbol Zn and atomic number 30. Zinc is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodi ...

is very important in human health, because zinc is present in the

structure A structure is an arrangement and organization of interrelated elements in a material object or system, or the object or system so organized. Material structures include man-made objects such as buildings and machines and natural objects such as ...

of some proteins like zinc-dependent

metalloenzymes Metalloprotein is a generic term for a protein that contains a metal ion cofactor. A large proportion of all proteins are part of this category. For instance, at least 1000 human proteins (out of ~20,000) contain zinc-binding protein domains al ...

and zinc-finger-containing transcriptional factors. In addition, zinc is involved in

signalling In signal processing, a signal is a function that conveys information about a phenomenon. Any quantity that can vary over space or time can be used as a signal to share messages between observers. The ''IEEE Transactions on Signal Processing'' ...

for

cell growth Cell growth refers to an increase in the total mass of a cell, including both cytoplasmic, nuclear and organelle volume. Cell growth occurs when the overall rate of cellular biosynthesis (production of biomolecules or anabolism) is greater than ...

, proliferation,

division Division or divider may refer to: Mathematics *Division (mathematics), the inverse of multiplication *Division algorithm, a method for computing the result of mathematical division Military *Division (military), a formation typically consisting ...

and

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

. As a result, any dysfunction of

s can be harmful for the cells, and some of them are associated with different

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...

and

inflammation Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...

. For instance, through activation of ZIP9,

testosterone Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testes and prostate, as well as promoting secondar ...

has been found to increase

levels in

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...

prostate cancer Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that sur ...

, and

ovarian follicle An ovarian follicle is a roughly spheroid cellular aggregation set found in the ovaries. It secretes hormones that influence stages of the menstrual cycle. At the time of puberty, women have approximately 200,000 to 300,000 follicles, each with th ...

cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery w ...

s and to induce

in these cells, an action which may be mediated partially or fully by increased zinc concentrations.

Gene mutations

Mutations In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...

in the SLC39A9 gene can occur due to

genetic deletion In genetics, a deletion (also called gene deletion, deficiency, or deletion mutation) (sign: Δ) is a mutation (a genetic aberration) in which a part of a chromosome or a sequence of DNA is left out during DNA replication. Any number of nucleoti ...

of the q24.1-24.3 band of base pairs within the human chromosome 14. This interstitial deletion

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...

deletes the SLC39A9 gene along with 18 other genes found close to the SLC39A9 gene on chromosome 14 Although specific gene associated diseases have not been determined, the deletion of this band causes diseases such as

congenital heart defects 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 ...

, mild

intellectual disability Intellectual disability (ID), also known as general learning disability in the United Kingdom and formerly mental retardation,Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010). is a generalized neurodevelopmental disorder characterized by signifi ...

brachydactyly Brachydactyly (Greek βραχύς = "short" plus δάκτυλος = "finger"), is a medical term which literally means "short finger". The shortness is relative to the length of other long bones and other parts of the body. Brachydactyly is an in ...

, and all patients with band deletion had

hypertelorism Hypertelorism is an abnormally increased distance between two organs or bodily parts, usually referring to an increased distance between the orbits (eyes), or orbital hypertelorism. In this condition the distance between the inner eye corners as ...

and a broad

nasal bridge The nasal bridge is the upper, bony part of the human nose, which overlies the nasal bones. Association with epicanthic folds Low-rooted nasal bridges are closely associated with epicanthic folds. A lower nasal bridge is more likely to cause an ...

. Patient specific clinical issues included ectopic organs, undescended testes, also called

cryptorchidism Cryptorchidism, also known as undescended testis, is the failure of one or both testes to descend into the scrotum. The word is from Greek () 'hidden' and () 'testicle'. It is the most common birth defect of the male genital tract. About 3% of ...

, and malrotation of the small intestine. Deletion mutation involving the SLC39A9 gene has also been reported in 23 cases of patients with circulation related cancers such as

B-cell lymphoma The B-cell lymphomas are types of lymphoma affecting B cells. Lymphomas are "blood cancers" in the lymph nodes. They develop more frequently in older adults and in immunocompromised individuals. B-cell lymphomas include both Hodgkin's lympho ...

and B-cell chronic lymphocytic leukaemia (CLL). Chimeric genes are a result of faulty

DNA replication In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms acting as the most essential part for biological inheritanc ...

, and arise when two or more coding sequences of the same or different chromosome combine in order to produce a single new gene. SLC39A9 forms a

chimeric gene Chimeric genes (literally, made of parts from different sources) form through the combination of portions of two or more coding sequences to produce new genes. These mutations are distinct from fusion genes which merge whole gene sequences into ...

product with a gene called PLEKHD1, that codes for an intracellular protein found within the

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 cerebel ...

. A study done in Seattle, USA, established the presence of the fusion protein product of the SLC39A9-PLEKHD1 gene to be present in 124 cases of

schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social withdra ...

and was closely related to the pathophysiology of disease. The fusion protein had features from both the parent genes and also possessed the ability to interact with cellular signalling pathways involving kinases such as

Akt Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transc ...

and Erk, leading to their increased phosphorylation within the brain and a consequent onset of schizophrenia. SLC39A9 gene also forms a fusion transcript with another gene called

MAP3K9 Mitogen-activated protein kinase kinase kinase 9 is an enzyme that in humans is encoded by the ''MAP3K9'' gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." m ...

, that encodes for MAP3 kinase enzyme. This SLC39A9-MAP3K9 fusion gene has a repetitive occurrence in breast cancers, demonstrated by a study done on 120 primary breast cancer samples from Korean women in 2015.

Cancer

Breast and prostate

A study in 2014, elucidated the intermediary role of ZIP9 in causing human

breast The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues. In females, it serves as the mammary gland, which produces and secret ...

and

, as it induced the

in the presence of testosterone in breast and prostate cancerous cells. unlike

ZIP1 Zinc transporter ZIP1 is a protein that in humans is encoded by the ''SLC39A1'' gene. The protein ZIP1 is responsible for the active transport of zinc into prostate cells. In many prostate cancer Prostate cancer is cancer of the prostate. Pros ...

, 2 and 3, ZIP9

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 ...

expression Expression may refer to: Linguistics * Expression (linguistics), a word, phrase, or sentence * Fixed expression, a form of words with a specific meaning * Idiom, a type of fixed expression * Metaphorical expression, a particular word, phrase, o ...

was increased in human prostate and breast

malignant Malignancy () is the tendency of a medical condition to become progressively worse. Malignancy is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not s ...

biopsy A biopsy is a medical test commonly performed by a surgeon, interventional radiologist, or an interventional cardiologist. The process involves extraction of sample cells or tissues for examination to determine the presence or extent of a diseas ...

cancer cells, which probably was because cells that divide rapidly require more zinc.

Brain

Treatment of glioblastoma cells with

TPEN TPEN (''N'',''N'',''N′'',''N′''-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine) is an intracellular membrane-permeable ion chelator. TPEN has a high affinity for many transition metals and should not be considered specific or selective ...

showed that

upregulation In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary proce ...

of ZIP9 in glioblastoma cells enhances

cell migration Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular dire ...

brain cancer A brain tumor occurs when abnormal cells form within the brain. There are two main types of tumors: malignant tumors and benign (non-cancerous) tumors. These can be further classified as primary tumors, which start within the brain, and secondar ...

by influencing

P53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...

and GSK-3ß, and also ERK and

AKT Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transc ...

signalling pathways Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a biochemical cascade, series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately re ...

phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...

after

activation Activation, in chemistry and biology, is the process whereby something is prepared or excited for a subsequent reaction. Chemistry In chemistry, "activation" refers to the reversible transition of a molecule into a nearly identical chemical or ...

B-cell receptor The B cell receptor (BCR) is a transmembrane protein on the surface of a B cell. A B cell receptor is composed of a membrane-bound immunoglobulin molecule and a signal transduction moiety. The former forms a type 1 transmembrane receptor protein, ...

Diabetes

Zinc must be constantly supplied to Pancreatic β-cells to function normally and maintain glycaemic control. The insulin secretory pathway in humans is highly dependent on zinc activities. The cells lose many zinc ions during the secretion of

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...

, and need to receive more zinc, and

of ZIP9

during this process increases. As a result, ZIP9, which is involved in importing zinc into the cells, is potentially a target for therapeutic studies in the future regarding diabetes type2.

References

{{Androgen receptor modulators G protein-coupled receptors Solute carrier family