Disruption of FLNB leads to skeletal malformation by interfering with skeletal segmentation through the HOX gene

Filamin B (FLNB) plays an important role in skeletal development. Mutations in FLNB can lead to skeletal malformation such as an abnormal number of ossification centers, indicating that the skeletal segmentation in the embryonic period may be interfered with. We established a mouse model with the pathogenic point mutation FLNB NM_001081427.1: c.4756G > A (p.Gly1586Arg) using CRISPR-Cas9 technology. Micro-CT, HE staining and whole skeletal preparation were performed to examine the skeletal malformation. In situ hybridization of embryos was performed to examine the transcription of HOX genes during embryonic development. The expression of FLNB was downregulated in FLNB^{G1586R/G1586R} and FLNB^WT/G1586R mice, compared to FLNB^WT/WT mice. Fusions in tarsal bones were found in FLNB^{G1586R/G1586R} and FLNB^WT/G1586R mice, indicating that the skeletal segmentation was interfered with. In the embryo of FLNB^{G1586R/G1586R} mice (E12.5), the transcription levels of HOXD10 and HOXB2 were downregulated in the carpal region and cervical spine region, respectively. This study indicated that the loss-of-function mutation G1586R in FLNB may lead to abnormal skeletal segmentation, and the mechanism was possibly associated with the downregulation of HOX gene transcription during the embryonic period.