O95972 (BMP15_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Bone morphogenetic protein 15
Short name=BMP-15

Alternative name(s):
Growth/differentiation factor 9B
Short name=GDF-9B

Gene names

Name:	BMP15
Synonyms:	GDF9B

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	392 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	May be involved in follicular development. Oocyte-specific growth/differentiation factor that stimulates folliculogenesis and granulosa cell (GC) growth. Ref.5
Subunit structure	Homodimer. But, in contrast to other members of this family, cannot be disulfide-linked. Ref.5
Subcellular location	Secreted.
Involvement in disease	Ovarian dysgenesis 2 (ODG2) [MIM:300510]: A disorder characterized by lack of spontaneous pubertal development, primary amenorrhea, uterine hypoplasia, and hypergonadotropic hypogonadism as a result of streak gonads. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.7 Premature ovarian failure 4 (POF4) [MIM:300510]: An ovarian disorder defined as the cessation of ovarian function under the age of 40 years. It is characterized by oligomenorrhea or amenorrhea, in the presence of elevated levels of serum gonadotropins and low estradiol. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.8 Ref.9 Ref.10 Ref.11 Ref.12
Miscellaneous	The mature protein migrates in two distinct mature proteins, P16 (16KDa) and P17 (17KDa). Ovarian physiology and fertility are controlled by endocrine and paracrine signals. These act in a species-dependent manner and determine the ovulation quota in different mammalian species. While humans, and mammals such as the cow or red deer, normally ovulate only one egg per cycle, other mammals such as mouse and pig can ovulate in excess of ten per cycle. The mechanisms that regulate the species-specific differences in the number of follicles that go onto ovulate during each reproductive cycle are poorly understood. According to Ref.6, mRNA expression levels of GDF9 and BMP15 are tightly co-regulated within each species and influence species-specific ovulation-rates.
Sequence similarities	Belongs to the TGF-beta family.

Ontologies

Keywords
Cellular component	Secreted
Disease	Disease mutation Premature ovarian failure
Domain	Signal
Molecular function	Cytokine Growth factor
PTM	Disulfide bond Glycoprotein Phosphoprotein Pyrrolidone carboxylic acid
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	female gamete generation Traceable author statement Ref.1. Source: ProtInc granulosa cell development Inferred from electronic annotation. Source: InterPro ovarian follicle development Inferred from electronic annotation. Source: InterPro
Cellular_component	extracellular space Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 18	18	Potential
	Propeptide	19 – 267	249			PRO_0000033892
	Chain	268 – 392	125	Bone morphogenetic protein 15		PRO_0000033893
Amino acid modifications
	Modified residue	268	1	Pyrrolidone carboxylic acid; in P16 and P17
	Modified residue	273	1	Phosphoserine; in P16 Ref.5
	Glycosylation	87	1	N-linked (GlcNAc...) Potential
	Glycosylation	147	1	N-linked (GlcNAc...) Potential
	Glycosylation	237	1	N-linked (GlcNAc...) Potential
	Glycosylation	277	1	O-linked (HexNAc...); in P17 Ref.5
	Glycosylation	373	1	N-linked (GlcNAc...) Potential
	Disulfide bond	291 ↔ 357		By similarity
	Disulfide bond	320 ↔ 389		By similarity
	Disulfide bond	324 ↔ 391		By similarity
Natural variations
	Natural variant	5	1	S → R Polymorphism with no or minor deleterious effect observed. Ref.11 Corresponds to variant rs113099187 [ dbSNP | Ensembl ].		VAR_058974
	Natural variant	61	1	R → Q in POF4. Ref.9		VAR_058975
	Natural variant	61	1	R → W in POF4. Ref.9		VAR_058976
	Natural variant	68	1	R → W in POF4; leads to marked reduction of mature protein production; does not generate a complete recovery of wild-type activity in granulosa cell line transfected with defective mutant and with equal amount of wild-type protein. Ref.10 Ref.11		VAR_058977
	Natural variant	76	1	R → C in POF4. Ref.9		VAR_058978
	Natural variant	76	1	R → H in POF4. Ref.9		VAR_058979
	Natural variant	103	1	N → S. Ref.1 Ref.9 Corresponds to variant rs41308602 [ dbSNP | Ensembl ].		VAR_058980
	Natural variant	138	1	R → H in POF4; leads to marked reduction of mature protein production; does not generate a complete recovery of wild-type activity in granulosa cell line transfected with defective mutant and with equal amount of wild-type protein. Ref.11		VAR_058981
	Natural variant	148	1	L → P in POF4; leads to marked reduction of mature protein production; does not generate a complete recovery of wild-type activity in granulosa cell line transfected with defective mutant and with equal amount of wild-type protein. Ref.8 Ref.11		VAR_058982
	Natural variant	180	1	A → F Requires 2 nucleotide substitutions. Ref.9		VAR_058983
	Natural variant	180	1	A → T in POF4; unknown pathological significance; no or minor deleterious effect detected. Ref.8 Ref.9 Ref.10 Ref.11		VAR_058984
	Natural variant	196	1	N → K in POF4. Ref.9		VAR_058985
	Natural variant	200	1	H → Y. Ref.12		VAR_066932
	Natural variant	206	1	R → H in POF4. Ref.9		VAR_058986
	Natural variant	221	1	W → R in POF4. Ref.9		VAR_058987
	Natural variant	235	1	Y → C in ODG2; dominant-negative effect; may cause relevant modifications in the conformation of the precursor protein possibly leading to altered processing and impaired activation of latent forms or to abnormal dimerization. Ref.7 Ref.10		VAR_021195
	Natural variant	243	1	I → V in POF4. Ref.9		VAR_058988
	Natural variant	263	1	L → LL No or minor deleterious effect detected. Ref.8 Ref.9 Ref.10 Ref.11		VAR_058989
	Natural variant	329	1	R → C in POF4. Ref.12		VAR_066933

Sequences

	Sequence		Length	Mass (Da)
	O95972 [UniParc]. Last modified August 16, 2004. Version 2. Checksum: A957275EF275A2E8	FASTA	392	45,055
	10 20 30 40 50 60 MVLLSILRIL FLCELVLFME HRAQMAEGGQ SSIALLAEAP TLPLIEELLE ESPGEQPRKP 70 80 90 100 110 120 RLLGHSLRYM LELYRRSADS HGHPRENRTI GATMVRLVKP LTNVARPHRG TWHIQILGFP 130 140 150 160 170 180 LRPNRGLYQL VRATVVYRHH LQLTRFNLSC HVEPWVQKNP TNHFPSSEGD SSKPSLMSNA 190 200 210 220 230 240 WKEMDITQLV QQRFWNNKGH RILRLRFMCQ QQKDSGGLEL WHGTSSLDIA FLLLYFNDTH 250 260 270 280 290 300 KSIRKAKFLP RGMEEFMERE SLLRRTRQAD GISAEVTASS SKHSGPENNQ CSLHPFQISF 310 320 330 340 350 360 RQLGWDHWII APPFYTPNYC KGTCLRVLRD GLNSPNHAII QNLINQLVDQ SVPRPSCVPY 370 380 390 KYVPISVLMI EANGSILYKE YEGMIAESCT CR

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The bone morphogenetic protein 15 gene is X-linked and expressed in oocytes." Dube J.L., Wang P., Elvin J., Lyons K.M., Celeste A.J., Matzuk M.M. Mol. Endocrinol. 12:1809-1817(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT SER-103.
[2]	"Human growth differentiation factor 9 (GDF-9) and its novel homolog GDF-9B are expressed in oocytes during early folliculogenesis." Aaltonen J., Laitinen M.P., Vuojolainen K., Jaatinen R., Horelli-Kuitunen N., Seppae L., Louhio H., Tuuri T., Sjoeberg J., Buetzow R., Hovatta O., Dale L., Ritvos O. J. Clin. Endocrinol. Metab. 84:2744-2750(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"The DNA sequence of the human X chromosome." Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D., Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A., Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G., Jones M.C. , Hurles M.E., Andrews T.D., Scott C.E., Searle S., Ramser J., Whittaker A., Deadman R., Carter N.P., Hunt S.E., Chen R., Cree A., Gunaratne P., Havlak P., Hodgson A., Metzker M.L., Richards S., Scott G., Steffen D., Sodergren E., Wheeler D.A., Worley K.C., Ainscough R., Ambrose K.D., Ansari-Lari M.A., Aradhya S., Ashwell R.I., Babbage A.K., Bagguley C.L., Ballabio A., Banerjee R., Barker G.E., Barlow K.F., Barrett I.P., Bates K.N., Beare D.M., Beasley H., Beasley O., Beck A., Bethel G., Blechschmidt K., Brady N., Bray-Allen S., Bridgeman A.M., Brown A.J., Brown M.J., Bonnin D., Bruford E.A., Buhay C., Burch P., Burford D., Burgess J., Burrill W., Burton J., Bye J.M., Carder C., Carrel L., Chako J., Chapman J.C., Chavez D., Chen E., Chen G., Chen Y., Chen Z., Chinault C., Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S., Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S., Corby N., Connor R.E., David R., Davies J., Davis C., Davis J., Delgado O., Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S., Draper H., Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I., Eades T., Ellwood M., Emery-Cohen A., Errington H., Evans K.L., Faulkner L., Francis F., Frankland J., Fraser A.E., Galgoczy P., Gilbert J., Gill R., Gloeckner G., Gregory S.G., Gribble S., Griffiths C., Grocock R., Gu Y., Gwilliam R., Hamilton C., Hart E.A., Hawes A., Heath P.D., Heitmann K., Hennig S., Hernandez J., Hinzmann B., Ho S., Hoffs M., Howden P.J., Huckle E.J., Hume J., Hunt P.J., Hunt A.R., Isherwood J., Jacob L., Johnson D., Jones S., de Jong P.J., Joseph S.S., Keenan S., Kelly S., Kershaw J.K., Khan Z., Kioschis P., Klages S., Knights A.J., Kosiura A., Kovar-Smith C., Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., Liu W., Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D., Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H., McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T., Milne S., Miner G., Mistry S.L., Morgan M., Morris S., Mueller I., Mullikin J.C., Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N., Okwuonu G., Palmer S., Pandian R., Parker D., Parrish J., Pasternak S., Patel D., Pearce A.V., Pearson D.M., Pelan S.E., Perez L., Porter K.M., Ramsey Y., Reichwald K., Rhodes S., Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K., Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D., Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R., Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T., Teague B., Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S., Tromans A.C., d'Urso M., Verduzco D., Villasana D., Waldron L., Wall M., Wang Q., Warren J., Warry G.L., Wei X., West A., Whitehead S.L., Whiteley M.N., Wilkinson J.E., Willey D.L., Williams G., Williams L., Williamson A., Williamson H., Wilming L., Woodmansey R.L., Wray P.W., Yen J., Zhang J., Zhou J., Zoghbi H., Zorilla S., Buck D., Reinhardt R., Poustka A., Rosenthal A., Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F., Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A., Nelson D.L., Weinstock G., Sulston J.E., Durbin R.M., Hubbard T., Gibbs R.A., Beck S., Rogers J., Bentley D.R. Nature 434:325-337(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[5]	"Characterization of the post-translational modification of recombinant human BMP-15 mature protein." Saito S., Yano K., Sharma S., McMahon H.E., Shimasaki S. Protein Sci. 17:362-370(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, PHOSPHORYLATION AT SER-273, GLYCOSYLATION AT THR-277, HOMODIMERIZATION.
[6]	"The ratio of growth differentiation factor 9: bone morphogenetic protein 15 mRNA expression is tightly co-regulated and differs between species over a wide range of ovulation rates." Crawford J.L., McNatty K.P. Mol. Cell. Endocrinol. 348:339-343(2012) [PubMed] [Europe PMC] [Abstract] Cited for: SPECIES-SPECIFIC OVULATION RATE DETERMINATION.
[7]	"Hypergonadotropic ovarian failure associated with an inherited mutation of human bone morphogenetic protein-15 (BMP15) gene." Di Pasquale E., Beck-Peccoz P., Persani L. Am. J. Hum. Genet. 75:106-111(2004) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT ODG2 CYS-235, CHARACTERIZATION OF VARIANT ODG2 CYS-235.
[8]	"Mutations and sequence variants in GDF9 and BMP15 in patients with premature ovarian failure." Laissue P., Christin-Maitre S., Touraine P., Kuttenn F., Ritvos O., Aittomaki K., Bourcigaux N., Jacquesson L., Bouchard P., Frydman R., Dewailly D., Reyss A.-C., Jeffery L., Bachelot A., Massin N., Fellous M., Veitia R.A. Eur. J. Endocrinol. 154:739-744(2006) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS POF4 PRO-148 AND THR-180, VARIANT LEU-263 INS.
[9]	"Missense mutations in the BMP15 gene are associated with ovarian failure." Dixit H., Rao L.K., Padmalatha V.V., Kanakavalli M., Deenadayal M., Gupta N., Chakrabarty B., Singh L. Hum. Genet. 119:408-415(2006) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS POF4 TRP-61; GLN-61; CYS-76; HIS-76; THR-180; LYS-196; HIS-206; ARG-221 AND VAL-243, VARIANTS SER-103; PHE-180 AND LEU-263 INS.
[10]	"Identification of new variants of human BMP15 gene in a large cohort of women with premature ovarian failure." Di Pasquale E., Rossetti R., Marozzi A., Bodega B., Borgato S., Cavallo L., Einaudi S., Radetti G., Russo G., Sacco M., Wasniewska M., Cole T., Beck-Peccoz P., Nelson L.M., Persani L. J. Clin. Endocrinol. Metab. 91:1976-1979(2006) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS POF4 TRP-68; THR-180 AND CYS-235, VARIANT LEU-263 INS.
[11]	"BMP15 mutations associated with primary ovarian insufficiency cause a defective production of bioactive protein." Rossetti R., Di Pasquale E., Marozzi A., Bione S., Toniolo D., Grammatico P., Nelson L.M., Beck-Peccoz P., Persani L. Hum. Mutat. 30:804-810(2009) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS POF4 TRP-68; HIS-138; PRO-148 AND THR-180, VARIANTS ARG-5 AND LEU-263 INS, CHARACTERIZATION OF VARIANTS POF4 TRP-68; HIS-138; PRO-148 AND THR-180, CHARACTERIZATION OF VARIANTS ARG-5 AND LEU-263 INS.
[12]	"Analyses of growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) mutation in Chinese women with premature ovarian failure." Wang B., Wen Q., Ni F., Zhou S., Wang J., Cao Y., Ma X. Clin. Endocrinol. (Oxf.) 72:135-136(2010) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT TYR-200, VARIANT POF4 CYS-329.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF082350, AF082349 Genomic DNA. Translation: AAC99768.1. AJ132405 Genomic DNA. Translation: CAB43531.1. AL359914 Genomic DNA. Translation: CAI41226.1. BC069155 mRNA. Translation: AAH69155.1. BC117264 mRNA. Translation: AAI17265.1. BC117266 mRNA. Translation: AAI17267.1.
IPI	IPI00001485.
RefSeq	NP_005439.2. NM_005448.2.
UniGene	Hs.532692.
3D structure databases
ProteinModelPortal	O95972.
ModBase	Search...
Protein-protein interaction databases
STRING	9606.ENSP00000252677.
PTM databases
PhosphoSite	O95972.
Proteomic databases
PaxDb	O95972.
PRIDE	O95972.
Protocols and materials databases
DNASU	9210.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000252677; ENSP00000252677; ENSG00000130385. ENST00000598029; ENSP00000469070; ENSG00000269479.
GeneID	9210.
KEGG	hsa:9210.
UCSC	uc011mnw.2. human.
Organism-specific databases
CTD	9210.
GeneCards	GC0XP050670.
HGNC	HGNC:1068. BMP15.
MIM	300247. gene. 300510. phenotype.
neXtProt	NX_O95972.
Orphanet	243. 46,XX gonadal dysgenesis. 619. Primary ovarian failure.
PharmGKB	PA25378.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG298347.
HOGENOM	HOG000095242.
HOVERGEN	HBG004660.
InParanoid	O95972.
KO	K05498.
OMA	SCHVEPW.
OrthoDB	EOG4HHP38.
PhylomeDB	O95972.
Enzyme and pathway databases
SignaLink	O95972.
Gene expression databases
Bgee	O95972.
CleanEx	HS_BMP15.
Genevestigator	O95972.
GermOnline	ENSG00000130385. Homo sapiens.
Family and domain databases
InterPro	IPR015923. BMP-15. IPR002405. Inhibin_asu. IPR001839. TGF-b_C. IPR015615. TGF-beta-rel. IPR017948. TGFb_CS. [Graphical view]
PANTHER	PTHR11848. PTHR11848. 1 hit. PTHR11848:SF22. PTHR11848:SF22. 1 hit.
Pfam	PF00019. TGF_beta. 1 hit. [Graphical view]
PRINTS	PR00669. INHIBINA.
SMART	SM00204. TGFB. 1 hit. [Graphical view]
PROSITE	PS00250. TGF_BETA_1. 1 hit. PS51362. TGF_BETA_2. 1 hit. [Graphical view]
ProtoNet	Search...
Other
GenomeRNAi	9210.
NextBio	34527.
SOURCE	Search...

Entry information

Entry name

BMP15_HUMAN

Accession

Primary (citable) accession number: O95972
Secondary accession number(s): Q17RM6, Q5JST1, Q9UMS1

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 1, 2000
Last sequence update:	August 16, 2004
Last modified:	May 29, 2013
This is version 114 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.