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

• Published in: Bone Reports Vol. 20; p. 101746
• Main Authors: Xu, Qiming, Cui, Lijia, Lin, Yude, Cui, Leigh-Anne, Xia, Weibo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2024; Elsevier
• Subjects: CRISPR-Cas9; Filamin B; HOX; In situ hybridization of embryo; Skeletal segmentation; HOX; In situ hybridization of embryo; Skeletal segmentation; Filamin B; CRISPR-Cas9
• ISSN: 2352-1872; 2352-1872
• DOI: 10.1016/j.bonr.2024.101746

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 FLNBG1586R/G1586R and FLNBWT/G1586R mice, compared to FLNBWT/WT mice. Fusions in tarsal bones were found in FLNBG1586R/G1586R and FLNBWT/G1586R mice, indicating that the skeletal segmentation was interfered with. In the embryo of FLNBG1586R/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. •A mouse model with the pathogenic point mutation G1586R in Filamin B (FLNB) was established using CRISPR-Cas9 technology.•Fusions in tarsal bones were found in FLNBG1586R/G1586R and FLNBWT/G1586R mice.•The transcription levels of HOXD10 and HOXB2 were downregulated in the embryo of FLNBG1586R/G1586R mice.•Disruption of FLNB may lead to abnormal skeletal segmentation by downregulating HOX gene during the embryonic period.