BMP4 mutations in tooth agenesis and low bone mass.

ABSTRACT:

Objective

To identify an uncommon genetic cause of tooth agenesis (TA) by utilizing whole exome sequencing (WES) and targeted Sanger sequencing in a cohort of 120 patients with isolated TA.

Design

One deleterious mutation in the gene encoding bone morphogenetic protein 4 (BMP4) was identified in 6 unrelated patients with TA by WES. After that, the coding exons of BMP4 were examined in 114 TA patients using Sanger sequencing. Dual-energy X-ray absorptiometry (DEXA) was used to measure the bone mineral density of patients who carried a BMP4 mutation. Finally, preliminary functional studies of two BMP4 mutants were performed.

Results

We detected 3 novel missense mutations (c.58 G > A: p.Gly20Ser, c.326 G > T: p.Arg109Leu and c.614 T > C: p.Val205Ala) and 1 reported mutation in the BMP4 gene among 120 TA probands. The previously reported BMP4 mutation (c.751C > T: p.His251Tyr) was associated with urethra and eye anomalies. By extending the pedigrees, we determined that the tooth phenotypes had an autosomal dominant inheritance pattern, as individuals carrying a BMP4 mutation exhibit different types of dental anomalies. Interestingly, we observed that patients harboring a BMP4 mutation manifested early onset osteopenia or osteoporosis. Further in vitro functional assays demonstrated that two BMP4 mutants resulted in a decreased activation of Smad signaling. Therefore, a loss-of-function in BMP4 may contribute to the clinical phenotypes seen in this study.

Conclusions

We identified 4 mutations in the BMP4 gene in 120 TA patients. To our knowledge, this is the first study to describe human skeletal diseases associated with BMP4 mutations.

SUBMITTER: Yu M 

PROVIDER: S-EPMC6639811 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature