Disruption of <i>FLNB</i> leads to skeletal malformation by interfering with skeletal segmentation through the <i>HOX</i> gene.
basic_science · Level V
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- Record sourced from PubMed, PMID 38463381.
- Also identified by DOI 10.1016/j.bonr.2024.101746 and PMC identifier 10924170.
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Abstract
Filamin B (FLNB) plays an important role in skeletal development. Mutations in <i>FLNB</i> 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 <i>FLNB</i> 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. <i>In situ</i> hybridization of embryos was performed to examine the transcription of <i>HOX</i> genes during embryonic development. The expression of <i>FLNB</i> was downregulated in <i>FLNB</i><sup><i>G1586R/G1586R</i></sup> and <i>FLNB</i><sup><i>WT/G1586R</i></sup> mice, compared to <i>FLNB</i><sup><i>WT/WT</i></sup> mice. Fusions in tarsal bones were found in <i>FLNB</i><sup><i>G1586R/G1586R</i></sup> and <i>FLNB</i><sup><i>WT/G1586R</i></sup> mice, indicating that the skeletal segmentation was interfered with. In the embryo of <i>FLNB</i><sup><i>G1586R</i>/<i>G1586R</i></sup> mice (E12.5), the transcription levels of <i>HOXD10</i> and <i>HOXB2</i> were downregulated in the carpal region and cervical spine region, respectively. This study indicated that the loss-of-function mutation G1586R in <i>FLNB</i> may lead to abnormal skeletal segmentation, and the mechanism was possibly associated with the downregulation of <i>HOX</i> gene transcription during the embryonic period.