Alternative titles; symbols
HGNC Approved Gene Symbol: BMP4
SNOMEDCT: 721878003;
Cytogenetic location: 14q22.2 Genomic coordinates (GRCh38): 14:53,949,736-53,956,891 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q22.2 | Microphthalmia, syndromic 6 | 607932 | Autosomal dominant | 3 |
| Orofacial cleft 11 | 600625 | 3 |
BMP4 is a vital regulatory molecule that functions throughout development in mesoderm induction, tooth development, limb formation, bone induction, and fracture repair. BMP4 is a member of the BMP family and transforming growth factor beta-1 (TGFB1; 190180) superfamily of secretory signaling molecules that play essential roles in embryonic development (summary by Bakrania et al., 2008).
Bakrania et al. (2008) stated that the BMP4 protein is 408 amino acids long and consists of a TGFB1 propeptide domain and a TGFB domain that forms an active dimer.
The transcriptional unit of the human BMP4 gene is encoded by 5 exons and spans approximately 7 kb (van den Wijngaard et al., 1996). The human BMP4 gene has at least 2 functional promoters, which are used in a cell type-specific manner.
Shore et al. (1998) determined that alternate first exons may be used and that the first 2 exons are untranslated. The promoter region is GC-rich and contains no obvious TATA or CAAT consensus sequences. Both positive and negative transcriptional regulatory elements are contained within the 5-prime flanking region.
Bakrania et al. (2008) stated that the BMP4 gene contains 4 exons. The first 2 exons are noncoding.
Dickinson et al. (1990) demonstrated that in the mouse the Bmp2b1 gene is located on chromosome 14 and maps to the same area as 'pug nose' (pn). The mutation in that disorder may reside in the Bmp2b1 gene. Arguing from homology of synteny, Dickinson et al. (1990) suggested that the human BMP2B1 gene may be located on chromosome 14. Furthermore, they suggested that a human homolog of the murine Bmp2b2 gene resides on the X chromosome, as it does in the mouse. There is, however, no direct evidence of a second BMP2B gene in the human (McAlpine, 1992).
By analysis of human/rodent somatic cell hybrids, Tabas et al. (1993) assigned the BMP4 gene to human chromosome 14. Using fluorescence in situ hybridization, van den Wijngaard et al. (1995) localized the BMP4 gene to 14q22-q23. By FISH, Shore et al. (1998) mapped the BMP4 gene to chromosome 14q21, a region more centromeric than previously reported.
Gross (2014) mapped the BMP4 gene to chromosome 14q22.2 based on an alignment of the BMP4 sequence (GenBank BC020546) with the genomic sequence (GRCh37).
Shafritz et al. (1996) found overexpression of BMP4 in lymphoblastoid cell lines from 26 of 32 patients with FOP (135100), but from only 1 of 12 normal subjects (P less than 0.001). Furthermore, BMP4 and its mRNA were detected in the lymphoblastoid cell lines from a man with FOP and his 3 affected children, but not from the children's unaffected mother. Cosegregation of DNA markers for the BMP4 locus on chromosome 14 in the rare families in which FOP is inherited would strengthen the candidacy of BMP4, and the demonstration of mutations in the BMP4 gene, especially in the promoter sequences, would be confirmatory.
In a series of expression studies in mouse, Tucker et al. (1998) demonstrated that BMP4 activates the expression of Msx1 (142983), leading to incisor tooth development. BMP4 inhibited expression of Barx1 (603260), which marks presumptive molar teeth, and limits expression to the proximal, presumptive molar mesenchyme at embryonic day 10. Fibroblast growth factor-8 (FGF8; 600483) stimulated Barx1 expression. When BMP4 signaling in early development was inhibited by application of exogenous noggin (NOG; 602991) protein, ectopic Barx1 expression resulted in transformation of tooth identity from incisor to molar.
Dlx1 (600029) and Dlx2 (126255) are involved in the patterning of murine dentition, since loss of these transcription factors results in early developmental failure in upper molar teeth. Thomas et al. (2000) found that Bmp4 was coexpressed with Dlx2 in distal oral epithelium and that it regulated Dlx2 expression by planar signaling. They presented evidence that Bmp4 and Fgf8 cooperate and regulate the strict expression of Dlx2 in the epithelium and the mesenchyme in the first branchial arch in developing mice.
Dooley et al. (2000) investigated the effect of BMP4 on androgen production in a human ovarian theca-like tumor (HOTT) cell culture model. BMP4 decreased forskolin-stimulated HOTT cell secretion of androstenedione and 17-alphahydroxyprogesterone (17OHP) by 50% but increased progesterone production 3-fold above forskolin treatment alone. BMP4 markedly inhibited forskolin stimulation of CYP17 (609300) expression but had little effect on 3-beta-HSD (see 109715), CYP11A1 (118485), or STAR (600617) protein levels. The authors identified the presence of mRNA for 3 BMP receptors in the HOTT cells model: BMPR1A (601299), BMPR1B (603248), and BMPR2 (600799). The authors concluded that BMP4 inhibits HOTT cell expression of CYP17, leading to an alteration of the steroidogenic pathway resulting in reduced androstenedione accumulation and increased progesterone production. They also noted that the effects of BMP4 seem similar to those caused by activin (see 147290), another member of the transforming growth factor-beta (TGFB; see 190180) superfamily of proteins.
In chick embryos, the first signs of left-right asymmetry are detected in Hensen's node, essentially by left-sided Sonic hedgehog (SHH; 600725) expression. After a gap of several hours, Shh induces polarized gene activities in the left paraxial mesoderm. Monsoro-Burq and Le Douarin (2001) showed that during this time period, Bmp4 signaling is necessary and sufficient to maintain Shh asymmetry within the node. Shh and Bmp4 proteins negatively regulate each other's transcription, resulting in a strict complementarity between these 2 gene patterns on each side of the node. Noggin, which is present in the midline at this stage, limits Bmp4 spreading. Moreover, Bmp4 is downstream to activin signals and controls Fgf8. Thus, the authors concluded that early Bmp4 signaling coordinates left and right pathways in Hensen's node.
Chen et al. (2002) studied BMP4 gene transfer and osteoinduction by BMP4 using an adenoviral vector to transduce mouse myoblast cells. BMP4 expressed by transduced myoblasts was located in the cytoplasm, and the differentiation pathway utilized by these cells was converted from a myogenic to an osteogenic pathway. Injection of the adenoviral vector carrying BMP4 into the hindlimb muscles of male athymic nude rats resulted in new bone formation that could be visualized on x-ray films as early as 3 weeks post injection. Histologic staining of bone tissue revealed a typical remodeled bone structure.
Cheng et al. (2003) measured the ability of 14 human BMPs to induce osteogenic transformation in a mouse pluripotential stem cell line, a mouse mesenchymal stem cell line, and a mature human osteoblastic cell line. Osteogenic activity was determined by measuring induction of alkaline phosphatase (see 171760), osteocalcin (112260), and matrix mineralization upon BMP stimulation. All BMPs except BMP3 (112263) and BMP12 (604651) were able to stimulate alkaline phosphatase activity in the mature osteoblasts. BMP4 was able to induce all markers of osteoblast differentiation in pluripotential and mesenchymal stem cells; however, BMP4 was a weaker inducer than BMP2 (112261), BMP6 (112266), and BMP9 (GDF2; 605120).
Paez-Pereda et al. (2003) stated that there is little doubt that estrogens and growth factors are involved in the control of lactotroph cell proliferation in the pituitary and that the tumorigenic action of estrogen in prolactinomas had been demonstrated by in vitro and clinical evidence. Thus, the number of lactotroph cells increases during pregnancy. Prolactinomas occur more frequently in women and increase in size during pregnancy or estrogen treatment, and, at least in human prolactinomas, estrogen receptor expression is positively related to size. Paez-Pereda et al. (2003) reported a previously undescribed mechanism for prolactinoma growth that involved BMP4, SMAD4 (600993), and estrogens.
By in situ hybridization, Zhu et al. (2004) found overlapping expression of Bmp4 and Nkx2.1 (600635) in embryonic mouse lung. They presented evidence that Nkx2.1 activated Bmp4 transcription through 2 Nkx2.1 elements in each of the 2 Bmp4 promoters.
Haramis et al. (2004) used mouse models to demonstrate that BMP4 expression occurs exclusively in the intravillus mesenchyme of the intestine. Villus epithelial cells respond to the BMP signal. Inhibition of BMP signaling by transgenic expression of noggin results in the formation of numerous ectopic crypt units perpendicular to the crypt-villus axis. These changes phenocopy the intestinal histopathology of patients with the cancer predisposition syndrome juvenile polyposis (174900), including the frequent occurrence of intraepithelial neoplasia. Many juvenile polyposis cases are known to harbor mutations in BMP pathway genes. Haramis et al. (2004) concluded that their data indicated that intestinal BMP signaling represses de novo crypt formation and polyp growth.
The mouse C3H10T1/2 stem cell line can be induced to differentiate into adipocytes by exposing proliferating cells to BMP4 during a specific time window prior to induction of differentiation (Tang et al., 2004). Bowers et al. (2006) identified a subclone of these cells, the A33 cell line, that was committed to the adipocyte lineage. A33 cells expressed and secreted Bmp4 during the critical time point in the proliferative stage. Inhibition of Bmp4 activity by the addition of noggin at the critical time blocked the ability of A33 cells to differentiate into adipocytes.
Piccirillo et al. (2006) reported that bone morphogenetic proteins, among which BMP4 elicits the strongest effect, trigger a significant reduction in the stem-like, tumor-initiating precursors of human glioblastomas. Transient in vitro exposure to BMP4 abolished the capacity of transplanted glioblastoma cells to establish intracerebral glioblastomas. Most importantly, in vivo delivery of BMP4 effectively blocked the tumor growth and associated mortality that occurred in 100% of mice after intracerebral grafting of human glioblastoma cells. Piccirillo et al. (2006) demonstrated that BMPs activate their cognate receptor BMPRs and trigger the SMAD signaling cascade in cells isolated from human glioblastomas. This is followed by a reduction in proliferation, and increased expression of markers of neural differentiation, with no effect on cell viability. The concomitant reduction in clonogenic ability, in the size of the CD133 (604365)-positive population, and in the growth kinetics of glioblastoma cells indicated that BMP4 reduces the tumor-initiating cell pool of glioblastomas. These findings showed that the BMP-BMPR signaling system--which controls the activity of normal brainstem cells--may also act as a key inhibitory regulator of tumor-initiating, stem-like cells from glioblastomas and the results also identified BMP4 as a novel, noncytotoxic therapeutic effector, which may be used to prevent growth and recurrence of glioblastomas in humans.
Wordinger et al. (2007) studied the effects of altered BMP signaling on intraocular pressure (IOP) in primary open angle glaucoma (POAG; see 137760). They found that the human trabecular meshwork (TM) synthesized and secreted BMP4 as well as expressed the BMP receptor subtypes BMPR1 (see BMPR1A; 601299) and BMPR2 (600799). TM cells responded to exogenous BMP4 by phosphorylating SMAD signaling proteins. Cultured human TM cells treated with TGFB2 significantly increased fibronectin (FN; 135600) levels, and BMP4 blocked this FN induction. There was significant elevation of mRNA and protein levels of the BMP antagonist Gremlin (GREM1; 603054) in glaucomatous TM cells. In addition, Gremlin was present in human aqueous humor. Gremlin blocked the negative effect of BMP4 on TGFB2 induction of FN. Addition of recombinant Gremlin to the medium of ex vivo perfusion-cultured human eye anterior segments caused the glaucoma phenotype of elevated IOP. Wordinger et al. (2007) concluded that these results were consistent with the hypothesis that, in POAG, elevated expression of Gremlin by TM cells inhibited BMP4 antagonism of TGFB2 and led to increased extracellular matrix deposition and elevated IOP.
Using RT-PCR, immunofluorescence, and flow cytometric analyses, Cejalvo et al. (2007) demonstrated that human thymus and cortical epithelial cells produced BMP2 and BMP4 and that both thymocytes and thymic epithelium expressed the molecular machinery to respond to these proteins. The receptors BMPR1A and BMPR2 were mainly expressed by cortical thymocytes, whereas BMPR1B was expressed in the majority of thymocytes. BMP4 treatment of chimeric human-mouse fetal thymic organ cultures seeded with CD34 (142230)-positive human thymic progenitors resulted in reduced cell recovery and inhibition of differentiation of CD4 (186940)/CD8 (see 186910) double-negative to double-positive stages. Cejalvo et al. (2007) concluded that BMP2 and BMP4 have a role in human T-cell differentiation.
A hair follicle cycles through anagen (growth), catagen (involution), and telogen (resting) phases and then reenters the anagen phase. Plikus et al. (2008) demonstrated that unexpected periodic expression of BMP2 and BMP4 in the dermis regulates the process of hair follicle regeneration. This BMP cycle is out of phase with the WNT/beta catenin cycle (see 116806), thus dividing the conventional telogen into new functional phases: one refractory and the other competent for hair regeneration, characterized by high and low BMP signaling, respectively. Overexpression of noggin (602991), a BMP antagonist, in mouse skin resulted in a markedly shortened refractory phase and faster propagation of the regenerative wave. Transplantation of skin from this mutant onto a wildtype host showed that follicles and donor and host can affect their cycling behaviors mutually, with the outcome depending on the equilibrium of BMP activity in the dermis. Administration of BMP4 protein caused the competent region to become refractory. The existence of a substance termed 'chalone' had been proposed to explain the phenomenon of telogen refractivity, which can inhibit anagen development. Plikus et al. (2008) suggested that BMPs may be the long-sought chalone postulated by classical experiments. Plikus et al. (2008) concluded that, taken together, the results presented in this study provided an example of hierarchical regulation of local organ stem cell homeostasis by the interorgan macroenvironment. The expression of Bmp2 in subcutaneous adipocytes indicates physiologic integration between the 2 thermoregulatory organs.
Using in situ hybridization in human embryos, Bakrania et al. (2008) authors demonstrated expression of BMP4 in optic vesicle, developing lens, the diencephalic floor, consistent with a role in pituitary development, and in the interdigital mesenchyme and the joint primordium at the stage at which limb buds have formed and are starting to differentiate into fingers. Because BMP4 interacts with hedgehog signaling genes in animals, Bakrania et al. (2008) evaluated gene expression in embryos and demonstrated cotemporal and cospatial expression of BMP4 and hedgehog signaling genes.
Wang et al. (2008) demonstrated binding between human full-length triple-helical type IV collagen (see 120130) and BMP4. Based on experiments in Drosophila, Wang et al. (2008) predicted that a conserved sequence in type IV collagen functions as a BMP-binding module, and that type IV collagens affect BMP signaling during vertebrate development.
Limb development is regulated by epithelial-mesenchymal feedback loops between sonic hedgehog (SHH; 600725) and fibroblast growth factor (FGF) signaling involving the bone morphogenetic protein antagonist Grem1. By combining mouse molecular genetics with mathematical modeling, Benazet et al. (2009) showed that BMP4 first initiates and SHH then propagates epithelial-mesenchymal feedback signaling through differential transcriptional regulation of Grem1 to control digit specification. This switch occurs by linking a fast BMP4/GREM1 module to the slower SHH/GREM1/FGF epithelial-mesenchymal feedback loop. This self-regulatory signaling network results in robust regulation of distal limb development that is able to compensate for variations by interconnectivity among the 3 signaling pathways.
Wandzioch and Zaret (2009) investigated how BMP4, transforming growth factor-beta (TGF-beta; 190180), and fibroblast growth factor signaling pathways converge on the earliest genes that elicit pancreas and liver induction in mouse embryos. These genes include ALB1 (103600), PROX1 (601546), HNF6 (604164), HNF1B (189907), and PDX1 (600733). The inductive network was found to be dynamic; it changed within hours. Different signals functioned in parallel to induce different early genes, and 2 permutations of signals induced liver progenitor domains, which revealed flexibility in cell programming. Also, the specification of pancreas and liver progenitors was restricted by the TGF-beta pathway.
Shox2 (602504) is essential for the formation of the sinoatrial valves and for the development of the pacemaking system of the heart. Puskaric et al. (2010) analyzed putative targets of Shox2 and identified Bmp4 as a direct target. Shox2 interacted directly with the Bmp4 promoter and activated transcription. Ectopic expression of Shox2 in Xenopus embryos stimulated transcription of Bmp4, and silencing of Shox2 in cardiomyocytes led to a reduction in the expression of Bmp4. Using Tbx5 (601620) del/+ mice, a model for Holt-Oram syndrome (142900), and Shox2 -/- mice, Puskaric et al. (2010) showed that the T-box transcription factor Tbx5 was a regulator of Shox2 expression in the inflow tract, and that Bmp4 was regulated by Shox2 in this compartment of the embryonic heart. In addition, Tbx5 acted cooperatively with Nkx2-5 (600584) to regulate the expression of Shox2 and Bmp4. Puskaric et al. (2010) concluded that their work established a functional link between Tbx5, Shox2, and Bmp4 in the pacemaker region of the developing heart.
Syndromic Microphthalmia 6
Bakrania et al. (2008) considered BMP4 as a candidate gene for ocular malformation and digit anomalies (MCOPS6; 607932) and screened 215 individuals with ocular defects, mainly microphthalmia, for cytogenetic defects by chromosomal analysis, for gene deletions by multiplex ligation-dependent probe amplification (MLPA), and for mutations in the BMP4 gene by direct sequencing. They identified 2 individuals with a 14q22-q23 deletion associated with anophthalmia-microphthalmia, 1 with associated pituitary anomaly. Sequence analysis of the BMP4 gene identified 2 mutations: a frameshift mutation (112262.0001) in a family with anophthalmia-microphthalmia, retinal dystrophy, myopia, poly- and/or syndactyly, and brain anomalies, and a missense mutation (112262.0002) in an individual with anophthalmia-microphthalmia and brain anomalies. The finding of expression of BMP4 in developing human optic vesicle, retina and lens, pituitary region, and digits strongly supported BMP4 as a causative gene for anophthalmia-microphthalmia with pituitary abnormalities and digit anomalies. Bakrania et al. (2008) also identified 4 cases, some of which had retinal dystrophy, with 'low penetrant' mutations in both BMP4 and hedgehog signaling genes, namely, Sonic hedgehog (SHH; 600725) or Patched (PTCH1; 601309). Bakrania et al. (2008) concluded that BMP4 is a major gene for anophthalmia-microphthalmia and/or retinal dystrophy and brain anomalies and may be a candidate for myopia and poly/syndactyly. The finding of low-penetrant variants of BMP4 and hedgehog signaling partners suggested an interaction between the 2 pathways in humans.
Reis et al. (2011) analyzed the BMP4 coding region in 133 patients with various ocular conditions, including 60 with clinical anophthalmia/microphthalmia (34 syndromic), 38 with anterior segment anomalies (including 3 patients with SHORT syndrome, 269880), 16 with cataract, 4 with coloboma, 5 with high myopia, and 10 with other disorders. In 1 patient with SHORT syndrome, they identified a heterozygous 2.263-Mb deletion encompassing BMP4 and 13 other genes. In 3 probands with syndromic microphthalmia, they identified heterozygosity for a 158-kb deletion involving only the BMP4 gene (112262.0006), a nonsense mutation (R198X; 112262.0007), and a frameshift mutation (112262.0008), respectively; the affected sister of the proband with the frameshift mutation carried both the frameshift and a missense mutation (H121R; 112262.0009).
Orofacial Cleft 11
Suzuki et al. (2009) identified mutations in the BMP4 gene (see, e.g., 112262.0003-112262.0005 and 112262.0007) in patients with cleft lip and cleft palate (OFC11; 600625). The parents, who also carried the mutation, had subtle defects in the orbicularis oris muscle on ultrasound. Overall, BMP4 mutations were identified in 1 of 30 patients with microform clefts, 2 of 87 patients with subepithelial defects in the orbicularis oris muscle, and 5 of 968 patients with overt cleft lip/palate (CL/P). These results indicated that microforms and subepithelial defects in the orbicularis oris muscle are part of the spectrum of CL/P and should be considered during the clinical evaluation of families with clefts.
Associations Pending Confirmation
In a patient with renal dysplasia, Schild et al. (2013) identified homozygosity for missense mutations in 2 genes: an R684C substitution in DACH1, and an N150K substitution in BMP4. At 4 years of age, the proband had anemia and renal insufficiency, and ultrasound revealed bilateral multiple cysts and hyperechogenic parenchyma. His kidney function deteriorated and he had end-stage renal disease by age 5. He underwent allogenic kidney graft 7 months later, and at age 19 continued to have good graft function. His parents were double cousins, and each carried both mutations in heterozygosity. Family history showed that his father had bilateral medullary renal cysts without impairment of renal function, and a second cousin had died shortly after birth from undefined renal cystic disease. The proband was the only family member homozygous for both mutations; however, an unaffected sister was homozygous for N150K in BMP4 and an unaffected maternal uncle was homozygous for R684C in DACH1, Both of these relatives had normal renal ultrasound and normal kidney function. Studies in transfected cells showed enhanced repression of TGF-beta (TGFB1; 190180) signaling with the DACH1 mutant compared to wildtype protein. Noting that the N150K substitution in BMP4 previously had been reported in homozygosity in a patient with renal dysplasia (Weber et al., 2008), Schild et al. (2013) suggested that the mutations might have acted synergistically in the development of the renal phenotype in their patient.
Connor (1996) speculated that transgenic mice with selective overexpression of Bmp4 may serve as animal models of fibrodysplasia ossificans progressiva (FOP; 135100) and may make it possible to evaluate potential therapies directed at influencing the expression of BMP4 or its 2 types of cell-surface receptors. Not only may this knowledge provide a rational basis for therapy for FOP, but possibly also measures for the control of local ectopic bone development, which occurs in 10 to 20% of patients who have undergone surgical hip replacement. According to Connor (1996), there appears to be an individual propensity to the phenomenon of secondary ectopic ossification of soft tissue. In the 10 to 20% of patients who develop local ectopic bone formation after hip replacement, if surgical removal of that bone is attempted or the opposite hip is replaced, ectopic bone almost invariably recurs or occurs.
Furuta and Hogan (1998) showed that Bmp4, which is expressed strongly in the mouse optic vesicle and weakly in surrounding mesenchyme and surface ectoderm, plays a crucial role in lens induction. In Bmp4-null mouse embryos, lens induction was absent but could be rescued by exogenous BMP4 protein applied into the optic vesicle in explant cultures. In Bmp4-null embryos, Msx2 (123101) expression was absent, and expression mutant eye explants was rescued by BMP4-carrying beads, suggesting that BMP4 functions to regulate specific gene expression in the optic vesicle. No change in Pax6 (607108) was detected in Bmp4-null eyes.
Using a hypomorphic Bmp4 allele and conditional gene inactivation, Jiao et al. (2003) circumvented the early lethality of Bmp4 null mouse embryos and manipulated Bmp4 expression specifically in developing cardiomyocytes. They found that Bmp4 was dispensable for cushion formation but was required for proper atrioventricular septation after cushions had formed. Defects in septation caused atrioventricular canal defects that recapitulated the range of AVCDs diagnosed in patients.
Kan et al. (2004) generated mice overexpressing BMP4 under the control of the neuron-specific enolase promoter (ENO2; 131360) and observed the development of progressive postnatal heterotopic endochondral ossification, a phenotype that matches the anatomic, spatial, and temporal characteristics of human FOP. The phenotype was completely rescued in double-transgenic mice that also overexpressed the BMP4 inhibitor noggin, confirming the role of BMP4 in the pathogenesis of the disease.
Liu et al. (2005) demonstrated that mice with conditional inactivation of the Bmpr1a gene in the facial primordia developed completely penetrant, bilateral cleft lip/palate (119530) with arrested tooth formation. The cleft secondary palate of Bmpr1a-mutant embryos was associated with diminished cell proliferation in maxillary process mesenchyme and defective anterior posterior patterning. In contrast, the mutant mice showed elevated apoptosis in the fusing lip region of the medial nasal process. Conditional inactivation of the Bmp4 gene resulted in delayed fusion of the medial nasal process to form the lip, resulting in isolated cleft lip in all mouse embryos at 12 days after conception. However, cleft lip was only present in 22% of mouse embryos at 14.5 days after conception, indicating spontaneous repair of cleft lip in utero (see 600625). The findings implicated a BMP4-BMPR1A genetic pathway that functions in lip fusion, and revealed that BMP signaling has distinct roles in lip and palate fusion.
Fuller et al. (2007) found that Bmp4 and Bmp7 (112267) increased rapidly at the site of chemically-induced demyelinating lesions in adult rat spinal cord. The Bmp proteins stimulated Smad (see, e.g., SMAD1; 601595) activation in mature astrocytes, resulting in increased expression of chondroitin sulfate proteoglycans and glial scar formation.
Goldman et al. (2009) used Bmp4-hypomorphic mice to investigate the regulation of hematopoietic stem cell (HSC) function and the maintenance of steady-state hematopoiesis in adults. Reporter gene analysis showed that Bmp4 was expressed in osteoblasts, endothelial cells, and megakaryocytes. Resting hematopoiesis was normal in Bmp4-deficient mice, but cells expressing Kit (164920) and Sca1 (also known as Ly6a, a mouse-specific gene) were significantly reduced. Serial transplantation revealed that Bmp4-deficient recipients had a microenvironmental defect that reduced the repopulating activity of wildtype HSCs. When wildtype HSCs did engraft in Bmp4-deficient bone marrow, they showed a marked decrease in functional stem cell activity. Goldman et al. (2009) concluded that BMP4 is a critical component of the hematopoietic microenvironment and is involved in regulating HSC number and function.
Bakrania et al. (2008) described a kindred in which members of 3 generations had eye, brain, and digit developmental anomalies (MCOPS6; 607932) related to a frameshift mutation in the BMP4 gene (222del2AG, S76fs104X). The proband had clinical anophthalmia with no light perception on the right; the left eye showed microcornea, coloboma, retinal dystrophy, and tilted optic disc. He had mild learning difficulties and polydactyly. Cranial MRI showed enlarged trigones, hypoplastic corpus callosum, and sulcal widening. The maternal grandmother, who carried the same mutation, showed on MRI enlarged ventricles, hypoplastic corpus callosum, and marked sulcal widening associated with diffuse brain atrophy; additionally, she had polydactyly and finger webbing.
In a patient with eye, brain, and digit developmental anomalies (MCOPS6; 607932), Bakrania et al. (2008) identified a 278A-G transition in the BMP4 gene that resulted in a glu93-to-gly substitution (E93G). The right eye of the patient showed microphthalmia, sclerocornea, and orbital cyst; the left eye showed microphthalmia, coloboma, and microcornea. Cranial MRI showed delayed myelination and mild reduction in white matter. The proband had developmental delay, seizures, undescended testes, simple prominent ears, broad hands, low-placed thumbs, and dysplastic nails.
In a child with a microform cleft lip and cleft palate (OFC11; 600625), Suzuki et al. (2009) identified a heterozygous 1037C-T transition in the BMP4 gene, resulting in an ala346-to-val (A346V) substitution. His father, who also carried the mutation, had subtle right microform cleft lip and a bifid uvula. The microform cleft lip was confirmed by ultrasound, which detected defects in the orbicularis oris muscle in both patients.
In a child with a cleft lip and cleft palate (OFC11; 600625), Suzuki et al. (2009) identified a heterozygous 271A-T transversion in the BMP4 gene, resulting in a ser91-to-cys (S91C) substitution. The child's parent, who also carried the mutation, had defects of the orbicularis oris muscle on ultrasonography.
In a child with a cleft lip and cleft palate (OFC11; 600625), Suzuki et al. (2009) identified a heterozygous 860G-A transition in the BMP4 gene, resulting in an arg287-to-his (R287H) substitution. The child's parent, who also carried the mutation, had defects of the orbicularis oris muscle on ultrasonography.
In a 12-year-old Caucasian girl with bilateral microphthalmia and other eye anomalies, facial dysmorphism, cognitive impairment, and a history of hypotonia (MCOPS6; 607932), Reis et al. (2011) identified heterozygosity for a 158-kb deletion on chromosome 14q22.2, with a minimum interval chr14:53,361,728-53,520,165 and a maximum interval chr14:53,352,059-53,520,859 (NCBI36), deleting only the BMP4 gene. In addition to bilateral microphthalmia, the patient had bilateral persistence of the pupillary membrane, high myopia, strabismus, and nystagmus. Her dysmorphic facial features included maxillary hypoplasia with midface flattening, thin upper lip, broad nasal bridge and tip, and telecanthus, with a preauricular ear tag on the right. She had normal growth, head circumference, umbilicus, hands, and feet. The patient was adopted, and no family members were available for study.
In a Mongolian patient with cleft lip and palate (OFC11; 600625), Suzuki et al. (2009) identified heterozygosity for a 592C-T transition in exon 4 of the BMP4 gene, resulting in an arg198-to-ter (R198X) substitution. The parents were unavailable for testing.
In a 19-month-old boy with right clinical anophthalmia and left microphthalmia, sclerocornea, facial asymmetry, and right-sided diaphragmatic hernia (MCOPS6; 607932), Reis et al. (2011) identified heterozygosity for the R198X mutation in BMP4. The boy also had mild to moderate laryngomalacia, with indentation from the innominate artery, and bilateral inguinal hernias. He was macrocephalic with a large anterior fontanel, and had hydrocephalus that was treated with a large subdural-peritoneal shunt. Brain MRI at 4 months of age confirmed the ocular findings and showed macrocrania with very prominent subarachnoid spaces, superimposed overlying subdural collections, as well as diffuse cerebral atrophy with ventricular prominence. The mutation was not found in 179 Caucasian, 89 African American, 91 Asian, and 93 Hispanic controls.
In a 3.5-year-old Caucasian girl with bilateral clinical anophthalmia, small ears, and small left renal cyst (MCOPS6; 607932), Reis et al. (2011) identified heterozygosity for a 1-bp duplication (171dupC) in exon 2 of the BMP4 gene, predicted to cause a frameshift and premature termination. The proband had normal development, without craniofacial dysmorphism or anomalies of the hands or feet. Head CT in the neonatal period showed significantly small globes, minimal ocular tissue, and absent optic nerves, but otherwise normal brain structures. Her affected 9-year-old maternal half sister was found to be compound heterozygous for 171dupC and a 362A-G transition in exon 2 of BMP4, resulting in a his121-to-arg (H121R; 112262.0009) substitution at a conserved residue. The sister had unilateral clinical anophthalmia, blepharophimosis, telecanthus, and bilateral postaxial polydactyly of the hands. She had poor growth, with height and weight less than the 3rd centile, and relative macrocephaly with frontal bossing. Head CT showed atrophic left globe and small left orbit. Their asymptomatic mother was heterozygous for the frameshift mutation, with no evidence of mosaicism; the mutation was apparently de novo, as the maternal grandparents carried wildtype BMP4 alleles. The mother was unavailable for examination, so mild ocular anomalies could not be ruled out, and the father was also unavailable for study. Neither mutation was found in 179 Caucasian, 89 African American, 91 Asian, and 93 Hispanic controls.
For discussion of the his121-to-arg (H121R) mutation in the BMP4 gene that was found in compound heterozygous state in a patient with syndromic microphthalmia (MCOPS6; 607932) by Reis et al. (2011), see 112262.0008.
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