Bone morphogenetic protein 15 (BMP-15) 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 BMP15

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 ...

. It is involved in

folliculogenesis :''Although the process is similar in many animals, this article will deal exclusively with human folliculogenesis.'' In biology, folliculogenesis is the maturation of the ovarian follicle, a densely packed shell of somatic cells that contains an ...

, the process in which primordial follicles develop into pre-ovulatory follicles.

Structure & Interactions

Structure

The BMP-15

is located on the X-chromosome and using Northern blot analysis BMP-15

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 ...

is locally expressed within the

ovaries The ovary () is a gonad in the female reproductive system that produces ova; when released, an ovum travels through the fallopian tube/oviduct into the uterus. There is an ovary on the left and the right side of the body. The ovaries are endocr ...

oocyte An oocyte (, oöcyte, or ovocyte) is a female gametocyte or germ cell involved in reproduction. In other words, it is an immature ovum, or egg cell. An oocyte is produced in a female fetus in the ovary during female gametogenesis. The female ger ...

s only after they have started to undergo the primary stages of development. BMP-15 is translated as a preproprotein that is composed of a single

peptide Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...

, which contains a proregion and a smaller mature region. Intracellular processing then leads to the removal of the proregion, leaving the biologically active mature region to perform the functions. This protein is a member of the Transforming growth factor beta (TGF-β) superfamily and is a paracrine signalling molecule. Most active BMPs have a common structure, in which they contain 7

cysteine Cysteine (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...

s, 6 of which form three intramolecular

disulphide bonds In chemistry, a disulfide (or disulphide in British English) is a compound containing a functional group or the anion. The linkage is also called an SS-bond or sometimes a disulfide bridge and usually derived from two thiol groups. In inorg ...

and the seventh being involved in the formation of dimers with other monomers. BMP-15 is an exception to this as the molecule does not contain the seventh cysteine. Instead in BMP-15 the fourth cysteine is replaced by a

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 − ...

Interactions

BMP-15 and GDF9 interact with each other and work synergistically to have similar interactions with the target cell. BMP15 can act as a

heterodimer In biochemistry, a protein dimer is a macromolecular complex or multimer formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ...

with GDF9 or on its own as a

homodimer In biochemistry, a protein dimer is a macromolecular complex or protein multimer, multimer formed by two protein monomers, or single proteins, which are usually Non-covalent interaction, non-covalently bound. Many macromolecules, such as proteins ...

. In most of the BMP family heterodimers and homodimers form as the seventh cysteine is involved in the formation of a

covalent bond A covalent bond is a chemical bond that involves the sharing of electrons to form electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs. The stable balance of attractive and repulsive forces between atom ...

, leading the

dimerization In chemistry, dimerization is the process of joining two identical or similar molecular entities by bonds. The resulting bonds can be either strong or weak. Many symmetrical chemical species are described as dimers, even when the monomer is u ...

. However, in the BMP-15 the homodimers form as a non-covalent bond is present between two BMP-15 subunits.

Function

Functions of BMP-15 include * Promotion of growth and maturation of

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. In humans, women have approximately 200,000 to 300,000 follicles at the time of puberty, ea ...

s, starting from the primary gonadotrophin-independent phases of

. * Regulation of the sensitivity of

granulosa cell A granulosa cell or follicular cell is a somatic cell of the sex cord that is closely associated with the developing female gamete (called an oocyte or egg) in the ovary of mammals. Structure and function In the Folliculogenesis#Primordial, primo ...

s to

follicle-stimulating hormone Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, puberty, pubertal maturat ...

(FSH) action, contributing to the determination of the number of eggs that are ovulated. * Prevention of granulosa cell

apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

Folliculogenesis

Folliculogenesis is an important process for the development and maintenance of

fertility Fertility in colloquial terms refers the ability to have offspring. In demographic contexts, fertility refers to the actual production of offspring, rather than the physical capability to reproduce, which is termed fecundity. The fertility rate ...

. Primordial follicles are stored in the ovary and throughout life are activated to go through morphological changes to become preovulatory follicles ready for

ovulation Ovulation is an important part of the menstrual cycle in female vertebrates where the egg cells are released from the ovaries as part of the ovarian cycle. In female humans ovulation typically occurs near the midpoint in the menstrual cycle and ...

, when the

is released into the

fallopian tube The fallopian tubes, also known as uterine tubes, oviducts or salpinges (: salpinx), are paired tubular sex organs in the human female body that stretch from the Ovary, ovaries to the uterus. The fallopian tubes are part of the female reproduct ...

of the female reproductive tract. BMP-15 main functions are crucial for the beginning of folliculogenesis as seen in Image 1. The primordial follicle is made up of the oocyte and a single layer of flattened granulosa cells. BMP-15 is released from the oocyte into the surrounding granulosa tissue where it binds to two membrane bound receptors on granulosa cells. This promotes granulosa cell proliferation via

mitosis Mitosis () is a part of the cell cycle in eukaryote, eukaryotic cells in which replicated chromosomes are separated into two new Cell nucleus, nuclei. Cell division by mitosis is an equational division which gives rise to genetically identic ...

. BMP-15 promotes the change of primordial to primary and secondary follicles which are surrounded by several granulosa cell layers but doesn't promote transition into preovulatory follicles. BMP-15 prevents differentiation into preovulatory follicle by inhibiting FSH action in granulosa. FSH is released by the

anterior pituitary The anterior pituitary (also called the adenohypophysis or pars anterior) is a major Organ (anatomy), organ of the endocrine system. The anterior pituitary is the glandular, Anatomical terms of location#Usage in human anatomy, anterior lobe that t ...

as part of the hypothalamic-pituitary-gonadal axis and promotes the differentiation of early follicles into later preovulatory ones. BMP-15 prevents this transition by inhibiting the production of FSH receptor mRNA in granulosa cells. Therefore, FSH cannot bind to the granulosa cells, this inhibits FSH dependent

progesterone Progesterone (; P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the ma ...

production and luteinization, subsequently granulosa cells do not differentiate. As BMP-15 acts directly on granulosa cells it has an important influence on granulosa function including

steroidogenesis A steroid is an organic compound with four fused rings (designated A, B, C, and D) arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter memb ...

inhibition of luteinization and differentiation of cumulus, without which would lead to infertility and lack of folliculogenesis.

Differences between species

The use of mammalian species other than human is often used in research to learn more about human biology.

Sheep

Two breeds of sheep, Inverdale and Hanna, are naturally

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 ...

carriers of

point mutation A point mutation is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a DNA or RNA sequence of an organism's genome. Point mutations have a variety of effects on the downstream protein product—consequences ...

s in the BMP-15 gene. These point mutations result in higher

rates and larger litter sizes than sheep strains with a

wildtype The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, "m ...

BMP-15

genotype The genotype of an organism is its complete set of genetic material. Genotype can also be used to refer to the alleles or variants an individual carries in a particular gene or genetic location. The number of alleles an individual can have in a ...

. This super-fertility was mimicked later through

immunization Immunization, or immunisation, is the process by which an individual's immune system becomes fortified against an infectious agent (known as the antigen, immunogen). When this system is exposed to molecules that are foreign to the body, called ' ...

of wildtype ewes against BMP-15 using various immunisation techniques. Sheep carrying

homozygous 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 ...

allele An allele is a variant of the sequence of nucleotides at a particular location, or Locus (genetics), locus, on a DNA molecule. Alleles can differ at a single position through Single-nucleotide polymorphism, single nucleotide polymorphisms (SNP), ...

s for the Inverdale and Hanna BMP-15 mutations are

infertile In biology, infertility is the inability of a male and female organism to reproduce. It is usually not the natural state of a healthy organism that has reached sexual maturity, so children who have not undergone puberty, which is the body's sta ...

, as they have streak ovaries and the primary stage of

is inhibited. These studies suggest that BMP-15 plays a vital role in the normal regulation of folliculogenesis and ovulation in sheep.

Mice

In mice, the BMP-15 homologue is not as physiologically important. Upon targeted deletion of a ''bmp15''

exon 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 ...

, the mice presented with only

subfertility In biology, infertility is the inability of a male and female organism to Sexual reproduction, reproduce. It is usually not the natural state of a healthy organism that has reached sexual maturity, so children who have not undergone puberty, whi ...

homozygotes 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 ...

and no clear aberrant phenotype in

heterozygotes 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 ...

. The homozygous mutant mice did not suffer from reduced folliculogenesis or impacted follicle progression, unlike in the sheep homologue

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, ...

experiments. The subfertility seen in the homozygous mutant phenotype was attributed to defective ovulation and reduced viability of embryos. Here it can be stated that BMP-15 is not as vital for normal female mouse fertility as it is for sheep.

Humans

Humans display a similar

phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological propert ...

to the Inverdale/Hanna sheep in regards to female fertility. In women, a mutation in BMP-15 is linked to hypergonadotropic ovarian failure due to ovarian dysgenesis. In this case, the researchers were able to identify that the father of the two sisters displaying this mutation had no documented phenotype associated with the mutation, so BMP-15 appears to only affect females. In slight contrast to the reports on sheep, the women in this study were heterozygous for the BMP-15 mutation but exhibited streak ovaries, a phenotype very similar to the one seen in homozygous

mutant In biology, and especially in genetics, a mutant is an organism or a new genetic character arising or resulting from an instance of mutation, which is generally an alteration of the DNA sequence of the genome or chromosome of an organism. It i ...

ewes. The sisters presented with primary amenorrhea, showing that BMP-15 is also vital to normal human female fertility, concordant with the sheep model.

Current theory

The main theory for this stark difference between mammalian species relates to the number of follicles normally ovulated in each cycle by each species. Humans and sheep are mono-ovulatory, potentially explaining the difference in litter size observed in mutant individuals. As mice are poly-ovulatory, the role of BMP-15 in female mouse fertility may not be as obvious.

Clinical relevance

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, ...

s within the

for BMP-15 have been associated with reproductive complications in females, due to the

X-linked Sex linkage describes the sex-specific patterns of inheritance and expression when a gene is present on a sex chromosome (allosome) rather than a non-sex chromosome ( autosome). Genes situated on the X-chromosome are thus termed X-linked, and ...

nature of the protein. Due to its role in

, mutations can lead to sub-fertility through decreased or absent folliculogenesis. In combination with GDF-9, mutant BMP-15 is also associated with

defects,

premature ovarian failure Primary ovarian insufficiency (POI), also called premature ovarian insufficiency and premature ovarian failure, is the partial or total loss of reproductive and hormonal function of the ovaries before age 40 because of follicular ( egg produc ...

and other reproductive pathologies. BMP-15 defects have been implicated in female sterility, Polycystic Ovary Syndrome (PCOS), primary ovarian insufficiency (POI) and

endometriosis Endometriosis is a disease in which Tissue (biology), tissue similar to the endometrium, the lining of the uterus, grows in other places in the body, outside the uterus. It occurs in women and a limited number of other female mammals. Endomet ...

. Women with PCOS have been noted to have higher levels of BMP-15, while missense mutations of the protein have been identified in females with POI. Research has also found inherited mutant BMP-15 to be involved with the pathogenesis of hypergonadotropic ovarian failure. This condition develops due to BMP-15 role in folliculogenesis, and the errors that occur when a mutant gene is inherited. The protein is linked to familial ovarian dysgenesis which results in hypergonadotropic ovarian failure. The importance of BMP-15 in ovulation and folliculogenesis has been highlighted by research into

Turner syndrome Turner syndrome (TS), commonly known as 45,X, or 45,X0,Also written as 45,XO. is a chromosomal disorder in which cells of females have only one X chromosome instead of two, or are partially missing an X chromosome (sex chromosome monosomy) lea ...

, a chromosomal abnormality where females are missing a complete or partial X chromosome. Depending on the chromosomal mutation, BMP-15 gene dosage varies and impacts ovarian development in Turner syndrome patients. The gene is thus involved in determining the extent of the ovarian defects present in Turner syndrome. BMP-15 is also present in animals and involved in reproduction, such as in mice and sheep. Reduced levels of BMP-15 in sheep have shown to increase ovulation, leading to larger litter sizes.

References

External links

* {{NLM content Developmental genes and proteins Bone morphogenetic protein TGFβ domain