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 residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

that in humans is encoded by the BMP15

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 ...

. 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 a ...

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

Structure & Interactions

Structure

The BMP-15

is located on the

X-chromosome The X chromosome is one of the two sex-determining chromosomes (allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and XO sex- ...

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 synthesizing a protein. mRNA is created during the ...

is locally expressed within the

ovaries 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. T ...

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 ...

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

preproprotein A protein precursor, also called a pro-protein or pro-peptide, is an inactive protein (or peptide) that can be turned into an active form by post-translational modification, such as breaking off a piece of the molecule or adding on another molecul ...

that is composed of a single

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. ...

, 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 formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, some ...

s, 6 of which form three intramolecular disulphide bonds 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 − for ...

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 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 ''dimer'' ha ...

with GDF9 or on its own as a

homodimer In biochemistry, a protein dimer is a macromolecular complex 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 ''dimer'' has ...

. 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 ato ...

, leading the

dimerization A dimer () ('' di-'', "two" + ''-mer'', "parts") is an oligomer consisting of two monomers joined by bonds that can be either strong or weak, covalent or intermolecular. Dimers also have significant implications in polymer chemistry, inorganic che ...

. 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. At the time of puberty, women have approximately 200,000 to 300,000 follicles, each with ...

s, starting from the primary

gonadotrophin Gonadotropins are glycoprotein hormones secreted by gonadotropic cells of the anterior pituitary of vertebrates. This family includes the mammalian hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH), the placental/chorionic ...

-independent phases of

. * Regulation of the sensitivity of granulosa cells 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, pubertal maturation, ...

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

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 in ...

Folliculogenesis

Folliculogenesis is an important process for the development and maintenance of

fertility Fertility is the capability to produce offspring through reproduction following the onset of sexual maturity. The fertility rate is the average number of children born by a female during her lifetime and is quantified demographically. Ferti ...

Primordial follicles :''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 ...

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

ovulation Ovulation is the release of eggs from the ovaries. In women, this event occurs when the ovarian follicles rupture and release the secondary oocyte ovarian cells. After ovulation, during the luteal phase, the egg will be available to be fertilize ...

, when the

is released into the

fallopian tube The fallopian tubes, also known as uterine tubes, oviducts or salpinges (singular salpinx), are paired tubes in the human female that stretch from the uterus to the ovaries. The fallopian tubes are part of the female reproductive system. In o ...

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 In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is maintai ...

. 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. Anatomy of the ovaries

BMP-15 prevents differentiation into preovulatory follicle by inhibiting FSH action in granulosa. FSH is released by the

anterior pituitary A major organ of the endocrine system, the anterior pituitary (also called the adenohypophysis or pars anterior) is the glandular, anterior lobe that together with the posterior lobe (posterior pituitary, or the neurohypophysis) makes up the pi ...

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 majo ...

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 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. ...

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—consequence ...

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, " ...

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 immunogen). When this system is exposed to molecules that are foreign to the body, called ''non-s ...

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. Mo ...

allele An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution. ::"The chrom ...

s for the Inverdale and Hanna BMP-15 mutations are

infertile Infertility is the inability of a person, animal or plant to reproduce by natural means. It is usually not the natural state of a healthy adult, except notably among certain eusocial species (mostly haplodiploid insects). It is the normal st ...

, 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 sequen ...

, the mice presented with only

subfertility Infertility is the inability of a person, animal or plant to Sexual reproduction, reproduce by natural means. It is usually not the natural state of a healthy adult, except notably among certain eusocial species (mostly haplodiploid insects). I ...

in homozygotes and no clear aberrant phenotype in heterozygotes. 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 strikin ...

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 (biology), morphology or physical form and structure, its Developmental biology, developmental proc ...

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 ...

ewes. The sisters presented with

primary amenorrhea Amenorrhea is the absence of a menstrual period in a woman of reproductive age. Physiological states of amenorrhoea are seen, most commonly, during pregnancy and lactation (breastfeeding). Outside the reproductive years, there is absence of menses ...

, 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, m ...

s within the

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

X-linked Sex linked describes the sex-specific patterns of inheritance and presentation when a gene mutation (allele) is present on a sex chromosome (allosome) rather than a non-sex chromosome (autosome). In humans, these are termed X-linked recessive, ...

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, premature menopause, and premature ovarian failure) is the partial or total loss of reproductive and hormonal function of the ovaries before age 40 because of fol ...

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 of the female reproductive system in which cells similar to those in the endometrium, the layer of tissue that normally covers the inside of the uterus, grow outside the uterus. Most often this is on the ovaries, fa ...

. 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), also known as 45,X, or 45,X0, is a genetic condition in which a female is partially or completely missing an X chromosome. Signs and symptoms vary among those affected. Often, a short and webbed neck, low-set ears, low h ...

, 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