Bioinformatics Database

BMP4: Bone morphogenetic protein 4

BMP4: Bone morphogenetic protein 4
3D Protein Structure Viewer​
Cellular Process
Tooth Eruption
Gene Name
BMP4: Bone morphogenetic protein 4
Gene ID
652
General Description
This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer. This protein regulates heart development and adipogenesis.
Alternative titles; symbols
BONE MORPHOGENETIC PROTEIN 2B; BMP2B BMP2B1
Chromosome
Chromosome 14
Cytogenetic location
14q22.2
Encoded Protein

Bone morphogenetic protein 4 isoform a preproprotein

https://www.ncbi.nlm.nih.gov/protein/NP_001193.2/

Function of the protein in oral and tooth development

It is know that BMP2 and BMP4 secreted by ectomesenchymal odontoblast cells play important roles in the expression of Enamel Matrix Proteins in ameloblasts. Hyun et al., (2019) reported that when gingival epithelial cells were treated with BMP2, BMP4, and TGFβ-1, the expression of ameloblast-specific markers was increased.

Fatemifar et al.,(2013) conducted genome-wide association study and report genetic variants at 15 loci associated with primary tooth eruption at genome-wide significant levels, including 8 novel variants within or near the following genes: BMP4, CACNB2, CDON, CALU/OPN1SW, AJUBA/C14orf93, DLEU7, TEX14/RAD51C and ADK.

During early tooth-germ development, MSX-1 becomes strongly expressed in mesenchyme at the lamina stage, achieves maximal expression during the cap stage. Msx1-deficient mice are characterized by arrest of tooth-germ development at the bud stage, along with decreased expression of bone morphogenetic protein 2 (Bmp2), bone morphogenetic protein 4 (Bmp4), lymphoid enhancer binding factor 1 (Lef1), and other downstream genes (Feng et al., 2018).

Bmp2, Bmp4, and Lef1 are highly expressed in dental mesenchyme at late bell stage. Msx1 is strongly expressed in multiple undifferentiated organs during development and its expression decreases when the dental germ begins to undergo differentiation. Feng et al,( 2018) suggest that MSX-1 inhibits the expression of Bmp2, Bmp4, and Lef1 in order to prevent the premature and excessive differentiation of odontoblasts that might otherwise be caused by their increased expression.

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 (Liu et al, 2005).

Dental and Oral Diseases

Orofacial cleft 11, OFC11
(OMIM ID: 600625)

OFC11 is an unusual anomaly consisting of a paramedian 'scar' of the upper lip with an appearance suggesting that a typical cleft lip was corrected in utero.This developmental anomaly is frequently associated with an ipsilateral notch in the vermilion border and a 'collapsed' nostril (Castilla and Martinez-Frias, 1995).

Protein Sequence
>NP_001193.2 bone morphogenetic protein 4 isoform a preproprotein [Homo sapiens]
MIPGNRMLMVVLLCQVLLGGASHASLIPETGKKKVAEIQGHAGGRRSGQSHELLRDFEATLLQMFGLRRR
PQPSKSAVIPDYMRDLYRLQSGEEEEEQIHSTGLEYPERPASRANTVRSFHHEEHLENIPGTSENSAFRF
LFNLSSIPENEVISSAELRLFREQVDQGPDWERGFHRINIYEVMKPPAEVVPGHLITRLLDTRLVHHNVT
RWETFDVSPAVLRWTREKQPNYGLAIEVTHLHQTRTHQGQHVRISRSLPQGSGNWAQLRPLLVTFGHDGR
GHALTRRRRAKRSPKHHSQRARKKNKNCRRHSLYVDFSDVGWNDWIVAPPGYQAFYCHGDCPFPLADHLN
STNHAIVQTLVNSVNSSIPKACCVPTELSAISMLYLDEYDKVVLKNYQEMVVEGCGCR
Mutations

ALA346VAL :
In a child with a microform cleft lip and cleft palate (OFC11), Suzuki et al. (2009) identified a heterozygous 1037C-T transition in the BMP4 gene, resulting in an ala346-to-val (A346V) substitution.

SER91CYS:
In a child with a cleft lip and cleft palate (OFC11), Suzuki et al. (2009) identified a heterozygous 271A-T transversion in the BMP4 gene, resulting in a ser91-to-cys (S91C) substitution.

ARG287HIS:
In a child with a cleft lip and cleft palate (OFC11), Suzuki et al. (2009) identified a heterozygous 860G-A transition in the BMP4 gene, resulting in an arg287-to-his (R287H) substitution.

ARG198TER:
In a Mongolian patient with cleft lip and palate (OFC11), 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.

Related Literature

Hyun et al., (2019). https://doi.org/10.1038/s41598-019-40091-x

Fatemifar et al.,(2013). https://doi.org/10.1093/hmg/ddt231

Feng et al., (2018). https://doi.org/10.1111/eos.12390

Liu et al., (2005). https://doi.org/10.1242/dev.01676

Castilla, E. E., & Martínez-Frías, M. L. (1995). https://doi.org/10.1002/ajmg.1320580203

Suzuki et al., (2009). https://doi.org/10.1016/j.ajhg.2009.02.002