Species: mouse
Mutation name: None
type: null mutation
fertility: infertile - ovarian defect
Comment: Soyun E. Yi et al 2001 reported that the type I BMP receptor BmprIB is essential for female reproductive function. Mice deficient in BmprIB exhibit irregular estrous cycles and an impaired pseudopregnancy response. BmprIB mutants produce oocytes that can be fertilized in vitro, but defects in cumulus expansion prevent fertilization in vivo. This defect is associated with decreased levels of aromatase production in granulosa cells. Unexpectedly, levels of mRNA for cyclooxygenase 2, an enzyme required for cumulus expansion, are increased. BmprIB mutants also exhibit a failure in endometrial gland formation. The expression of BmprIB in uterine linings suggests that these defects are a direct consequence of loss of BMP signaling in this tissue. In summary, these studies demonstrate the importance of BMP signaling pathways for estrus cyclicity, estradiol biosynthesis, and cumulus cell expansion in vivo and reveal sites of action for BMP signaling pathways in reproductive tissues.

Species: human
Mutation name: None
type: None
fertility: fertile
Comment: Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2Lehmann K, et al . Freire-Maia N, et al reported a large Brazilian kindred of German origin with 117 individuals with the A2 (Mohr-Wriedt) bradydactyly . Some drawings based on radiographs and revealing the high phenotypic spectrum of the malformation are presented. Our corrected data suggest the presence of a segregation distortion in favor of the affected among the daughters of affected mothers (45:25; x12 = 5.71). This apparent anomalous segregation is not significant in the other comparisons made, although the p values corresponding to the x12 for two of them (78:56 and 109:83) are near 5%. Other 'similar' (although possibly different on the genetic aspect) A2 cases in the literature do not present any evidence of anomalous segregation. The dermatoglyphic disturbances verified in the affected index fingers seem to be mere allophenes of the basic dysmorphogenetic process which leads to the (autophenic) bone malformations. There is no birth order effect on the affected. Fertility seems to be higher among them than among their normal sibs.

Species: mouse
Mutation name: None
type: null mutation
fertility: subfertile
Comment: Granulosa Cell-Expressed BMPR1A and BMPR1B Have Unique Functions in Regulating Fertility but Act Redundantly to Suppress Ovarian Tumor Development. Edson MA et al. Bone morphogenetic proteins (BMPs) have diverse roles in development and reproduction. Although several BMPs are produced by oocytes, thecal cells, and granulosa cells of developing follicles, the in vivo functions of most of these ligands are unknown. BMP signals are transduced by multiple type I and type II TGFbeta family receptors, and of the type I receptors, BMP receptor 1A (BMPR1A) and BMP receptor 1B (BMPR1B) are known to be expressed in rodent granulosa cells. Female mice homozygous null for Bmpr1b are sterile due to compromised cumulus expansion, but the function of BMPR1A in the ovary is unknown. To further decipher a role for BMP signaling in mouse granulosa cells, we deleted Bmpr1a in the granulosa cells of the ovary and found Bmpr1a conditional knockout females to be subfertile with reduced spontaneous ovulation. To explore the redundant functions of BMP receptor signaling in the ovary, we generated Bmpr1a Bmpr1b double-mutant mice, which developed granulosa cell tumors that have evidence of increased TGFbeta and hedgehog signaling. Thus, similar to SMAD1 and SMAD5, which have redundant roles in suppressing granulosa cell tumor development in mice, two type I BMP receptors, BMPR1A and BMPR1B, function together to prevent ovarian tumorigenesis. These studies support a role for a functional BMP signaling axis as a tumor suppressor pathway in the ovary, with BMPR1A and BMPR1B acting downstream of BMP ligands and upstream of BMP receptor SMADs.

Species: porcine
Mutation name: None
type: naturally occurring
fertility: fertile
Comment: Microarray profiling for differential gene expression in PMSG-hCG stimulated preovulatory ovarian follicles of Chinese Taihu and Large White sows. Sun X et al. ABSTRACT: BACKGROUND: The Chinese Taihu is one of the most prolific pig breeds in the world, which farrows at least five more piglets per litter than Western pig breeds partly due to a greater ovulation rate. Variation of ovulation rate maybe associated with the differences in the transcriptome of Chinese Taihu and Large White ovaries. In order to understand the molecular basis of the greater ovulation rate of Chinese Taihu sows, expression profiling experiments were conducted to identify differentially expressed genes in ovarian follicles at the preovulatory stage of a PMSG-hCG stimulated estrous cycle from 3 Chinese Taihu and 3 Large White cycling sows by using the Affymetrix Porcine GenechipTM. RESULTS: One hundred and thirty-three differentially expressed genes were identified between Chinese Taihu and Large White sows by using Affymetrix porcine GeneChip (p [less than or equal to] 0.05, Fold change [greater than or equal to] 2 or [less than or equal to] 0.5). Gene Ontology (GO) analysis revealed that these genes belonged to the class of genes that participated in regulation of cellular process, regulation of biological process, biological regulation, developmental process, cell communication and signal transduction and so on. Significant differential expression of 6 genes including WNT10B and DKK2 in the WNT signaling pathway was detected. Real-time RT-PCR confirmed the expression pattern in seven of eight selected genes. A search of chromosomal location revealed that 92 differentially expressed transcripts located to the intervals of quantitative trait loci (QTLs) for reproduction traits. Furthermore, SNPs of two differentially expressed genes- BAX and BMPR1B were showed to be associated with litter size traits in Large White pigs and Chinese DIV line pigs (p [less than or equal to] 0.1 or p [less than or equal to] 0.05). CONCLUSIONS: Our study detected many genes that showed differential expression between ovary follicles of two divergent breeds of pigs. Genes involved with regulation of cellular process, regulation of biological process, in addition to several genes not previously associated with ovarian physiology or with unknown function, were differentially expressed between two breeds. The suggestive or significant associations of BAX and BMPR1B gene with litter size indicated these genetic markers had the potentials to be used in pig industry after further validation of their genetic effects. Taken together, this study reveals many potential avenues of investigation for seeking new insights into ovarian physiology and the genetic control of reproduction.

Species: ovine
Mutation name:
type: naturally occurring
fertility: fertile
Comment: Smad4 Feedback Enhances BMPR1B Transcription in Ovine Granulosa Cells. Abdurahman A et al. (2019) BMPR1B is a type 1B receptor of the canonical bone morphogenetic protein (BMP)/Sma- and mad-related protein (Smad) signaling pathway and is well known as the first major gene associated with sheep prolificacy. However, little is known about the transcriptional regulation of the ovine BMPR1B gene. In this study, we identified the ovine BMPR1B gene promoter and demonstrated that its transcription was regulated by Smad4. In sheep ovarian follicles, three transcriptional variants of BMPR1B gene with distinct transcription start sites were identified using 5' RACE assay while variants II and III were more strongly expressed. Luciferase assay showed that the region -405 to -200 nt is the PII promoter region of variant II. Interestingly, two putative Smad4-binding elements (SBEs) were detected in this region. Luciferase and ChIP assay revealed that Smad4 enhances PII promoter activity of the ovine BMPR1B gene by directly interacting with SBE1 motif. Furthermore, in the ovine granulosa cells, Smad4 regulated BMPRIB expression, and BMPRIB-mediated granulosa cells apoptosis. Overall, our findings not only characterized the 5' regulatory region of the ovine BMPR1B gene, but also uncovered a feedback regulatory mechanism of the canonical BMP/Smad signaling pathway and provided an insight into the transcriptional regulation of BMPR1B gene and sheep prolificacy.////////////////// Wilson T, et al 2001 reported that highly prolific booroola sheep have a mutation in the intracellular kinase domain of bone morphogenetic protein Ib receptor (ALK-6) that is expressed in both oocytes and granulosa cells. The Booroola fecundity gene (FecB) increases ovulation rate and litter size in sheep and is inherited as a single autosomal locus. The effect of FecB is additive for ovulation rate (increasing by about 1.6 corpora lutea per cycle for each copy) and has been mapped to sheep chromosome 6q23-31, which is syntenic to human chromosome 4q21-25. Bone morphogenetic protein IB (BMP-IB) receptor (also known as ALK-6), which binds members of the transforming growth factor-beta (TGF-beta) superfamily, is located in the region containing the FecB locus. Booroola sheep have a mutation (Q249R) in the highly conserved intracellular kinase signaling domain of the BMP-IB receptor. The mutation segregated with the FecB phenotype in the Booroola backcross and half-sib flocks of sheep with no recombinants. The mutation was not found in individuals from a number of sheep breeds not derived from the Booroola strain. BMPR-IB was expressed in the ovary and in situ hybridization revealed its specific location to the oocyte and the granulosa cell. Expression of mRNA encoding the BMP type II receptor was widespread throughout the ovary. The mutation in BMPR-IB found in Booroola sheep is the second reported defect in a gene from the TGF-beta pathway affecting fertility in sheep following the recent discovery of mutations in the growth factor, GDF9b/BMP15. Mulsant P, et al 2001 reported that the FecB locus is situated in the region of ovine chromosome 6 corresponding to the human chromosome 4q22-23 that contains the bone morphogenetic protein receptor IB (BMPR-IB) gene encoding a member of the transforming growth factor-beta (TGF-beta) receptor family. A nonconservative substitution (Q249R) in the BMPR-IB coding sequence was found to be associated fully with the hyperprolificacy phenotype of Booroola ewes. In vitro, ovarian granulosa cells from FecB(B)/FecB(B) ewes were less responsive than granulosa cells from FecB(+)/FecB(+) ewes to the inhibitory effect on steroidogenesis of GDF-5 and BMP-4, natural ligands of BMPR-IB. It is suggested that in FecB(B)/FecB(B) ewes, BMPR-IB would be inactivated partially, leading to an advanced differentiation of granulosa cells and an advanced maturation of ovulatory follicles. Souza CJ, et al selected the gene encoding the Bone Morphogenetic Protein receptor (BMPR) type 1 B (ALK-6) as a candidate site for the mutation. The BMPR1B gene in the human is located at the region linked with the Booroola mutation, syntenic to chromosome 6 in the sheep. A fragment of the sheep BMPR1B gene was cloned from an ovarian cDNA and the deduced aminoacid (AA) sequence is over 98% homologous to the known mammalian sequences. cDNA and genomic DNA from 20 Booroola genotypes were screened and two point mutation were found in the kinase domain of the receptor, one at base 746 of the coding region (A in the ++ to a G in FF animals) which results in a change from a glutamine in the wild type to a arginine in the Booroola animals. Another point mutation was identified at position 1113, (C to A) but this mutation does not change the coding aminoacid. The first mutation was confirmed in genomic DNA from 10 ewes from an independent Brazilian flock which segregates the Booroola phenotype. In all instances homozygous FecB gene carrier (n=11) had only the 746 A to G mutation, non gene carriers (n=14) had only the wild type sequence and heterozygote gene carriers (n=5) had both sequences. This mutation in the subdomain 3 of the kinase domain could result in an alteration in the expression and/or phosphorylation of SMADs, resulting in the phenotype characteristic of the Booroola animals which is the 'precocious' development of a large number of small antral follicles resulting in increased ovulation rate. Enhanced response of granulosa and theca cells from sheep carriers of the FecB mutation in vitro to gonadotrophins and BMP-2,4 and 6 Campbell BK, et al . The FecB (Booroola) mutation, which leads to increased ovulation rates and multiple births in sheep, is now known to occur in the signaling domain of the BMP-1B receptor. We examined the effect of the mutation on the responsiveness of granulosa (GC) and theca (TC) cells to BMPs and other local regulators using tissue from animals with (FF) and without (2+) the FecB mutation. Experiments examined the effect of BMPs 2, 4 and 6 (0.005-50 ng/ml), and their interaction with IGF-1 (0.1-10 ng/ml LR3 analog) and gonadotropins, on the proliferation and differentiation of GC and TC isolated from small (<2 mm) antral follicles and maintained in serum-free culture for up to 8 days. Dose finding studies using ovaries from wild-type sheep obtained from the abbattoir showed no difference between the different BMPs in stimulating (P < 0.001) estradiol (E2) production by GC cultured with FSH (10 ng/ml) but there was a clear interaction (P < 0.001) with IGF-1. BMPs had no effect on GC proliferation or the sensitivity of GCs to FSH. In contrast, higher doses of BMP's (5-50 ng/ml) inhibited LH-stimulated androstenedione (A4) production by TC whereas lower doses (0.005-0.05 ng/ml) stimulated TC proliferation (P < 0.01). Regardless of dose of IGF-1, at the end of culture (96-192 h) hormone production by GC (E2, inhibin A) and TC (A4) was 4- to 5-fold greater (P < 0.001) by cells from FF compared with 2+ ewes exposed to the same dose of gonadotropin. In the presence of low concentrations of IGF-1 (0.1 ng/ml), the maximum increase in the production of E2 and Inhibin A by granulosa cells from FF ewes in response to BMPs was observed at doses that were 3-10 fold lower (3-10 ng/ml) than 2+ (30 ng/ml; P < 0.001). Low doses of BMPs stimulated proliferation of TC from 2+ (P < 0.01) but not FF ewes. Immunohistochemistry confirmed BMP-6 protein expression in the oocyte, granulosa and thecal layers of antral follicles from both genotypes. These results confirm a major role for BMPs in controlling ovarian somatic cell function in sheep and provide evidence to support the hypothesis that the FecB mutation increases the BMP response of somatic cells when stimulated to differentiate by gonadotropins.

Species: other
Mutation name:
type: null mutation
fertility: infertile - ovarian defect
Comment: Mutation in the type IB bone morphogenetic protein receptor alk6b impairs germ-cell differentiation and causes germ-cell tumors in zebrafish. Neumann JC et al. Germ-cell tumors (GCTs), which arise from pluripotent embryonic germ cells, exhibit a wide range of histologic differentiation states with varying clinical behaviors. Although testicular GCT is the most common cancer of young men, the genes controlling the development and differentiation of GCTs remain largely unknown. Through a forward genetic screen, we previously identified a zebrafish mutant line, tgct, which develops spontaneous GCTs consisting of undifferentiated germ cells [Neumann JC, et al. (2009) Zebrafish 6:319-327]. Using positional cloning we have identified an inactivating mutation in alk6b, a type IB bone morphogenetic protein (BMP) receptor, as the cause of the zebrafish GCT phenotype. Alk6b is expressed in spermatogonia and early oocytes, and alk6b mutant gonads display impaired BMP signal transduction, altered expression of BMP target genes, and abnormal germ-cell differentiation. We find a similar absence of BMP signaling in undifferentiated human GCTs, such as seminomas and embryonal carcinoma, but not in normal testis or in differentiated GCTs. These results indicate a germ-cell-autonomous role for BMP signal transduction in germ-cell differentiation, and highlight the importance of the BMP pathway in human GCTs.

Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: New mutations in non-syndromic primary ovarian insufficiency patients identified via whole-exome sequencing. Patiño LC et al. (2017) Is it possible to identify new mutations potentially associated with non-syndromic primary ovarian insufficiency (POI) via whole-exome sequencing (WES)? WES is an efficient tool to study genetic causes of POI as we have identified new mutations, some of which lead to protein destablization potentially contributing to the disease etiology. POI is a frequently occurring complex pathology leading to infertility. Mutations in only few candidate genes, mainly identified by Sanger sequencing, have been definitively related to the pathogenesis of the disease. This is a retrospective cohort study performed on 69 women affected by POI. WES and an innovative bioinformatics analysis were used on non-synonymous sequence variants in a subset of 420 selected POI candidate genes. Mutations in BMPR1B and GREM1 were modeled by using fragment molecular orbital analysis. Fifty-five coding variants in 49 genes potentially related to POI were identified in 33 out of 69 patients (48%). These genes participate in key biological processes in the ovary, such as meiosis, follicular development, granulosa cell differentiation/proliferation and ovulation. The presence of at least two mutations in distinct genes in 42% of the patients argued in favor of a polygenic nature of POI. It is possible that regulatory regions, not analyzed in the present study, carry further variants related to POI. WES and the in silico analyses presented here represent an efficient approach for mapping variants associated with POI etiology. Sequence variants presented here represents potential future genetic biomarkers. This study was supported by the Universidad del Rosario and Colciencias (Grants CS/CIGGUR-ABN062-2016 and 672-2014). Colciencias supported Liliana Catherine Patiño´s work (Fellowship: 617, 2013). The authors declare no conflict of interest./ . Table 1 /////////////////

Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: BMPR1A and BMPR1B missense mutations cause primary ovarian insufficiency. Renault L et al. (2019) Primary ovarian insufficiency (POI) is a frequently occurring disorder affecting ~1% of women under 40 years of age. POI, which is characterized by the premature depletion of ovarian follicles and elevated plasma levels of FSH, leads to infertility. Although various etiological factors have been described, including chromosomal abnormalities and gene mutations, most cases remain idiopathic. To identify and to validate functionally new sequence variants in two genes playing a key role in mammalian ovarian function, BMPR1A and 1B (bone morphogenic protein receptor), leading to POI. The impact on BMP signaling of BMPR1A and 1B variants, previously identified by whole-exome sequencing on 69 women affected by isolated POI, was established by different in vitro functional experiments. We demonstrate that the BMPR1A-p.Arg442His and BMPR1B-p.Phe272Leu variants are correctly expressed and located but lead to an impairment of downstream BMP signaling. In accordance with infertility observed in mice lacking Bmpr1a in the ovaries and in Bmpr1b-/- mice, our results unveil for the first time, a link between BMPR1A and 1B variants and POI´s origin. We show that BMP signaling impaired through specific BMPR1A and B variants is a novel pathophysiological mechanism involved in human POI. We consider that BMPR1A and BMPR1B variants constitute genetic biomarkers of POI´s origin with clinical utility.//////////////////

Species: ovine
Mutation name:
type: naturally occurring
fertility: fertile
Comment: Polymorphisms in BMPR-IB gene and their association with litter size trait in Chinese Hu sheep. Yang Z et al. (2020) Identification and utilization of sheep major fecundity genes offer opportunities for the increase in litter size, as well as the improvement of production efficiency in livestock industry. BMPR-IB gene belongs to the TGF-β superfamily, and is also considered as a regulator for sheep reproductive performance due to its involvement in the mammalian gametogenesis pathway. This study aimed to detect the variations of BMPR-IB gene in Hu sheep (N = 934) and to evaluate their effects on the litter size trait. qRT-PCR results showed that the mRNA expression level of BMPR-IB in kidney was the highest. And in the tissues of ovary and pituitary, the expression levels of prolific group were significantly higher than that of non-prolific group (p < 0.05). Through DNA sequencing and PCR-RFLP, three SNPs were identified in the genomic region of BMPR-IB gene; the individuals with CC in g.29362047T > C, AA in g.29427689G > A and GG in FecB had better fecundity characterization. Additionally, association analysis indicated that two diplotypes of Hap2/2 and Hap2/4 showed larger litter size. Overall, our results verified several useful markers which would contribute to further development of sheep breeding strategies.//////////////////

Species: ovine
Mutation name:
type: naturally occurring
fertility: fertile
Comment: The expression and mutation of BMPR1B and its association with litter size in small-tail Han sheep (Ovis aries). Wen YL et al. (2021)//////////////////