Disruption of Leads to Skeletal Malformation by Interfering with Skeletal Segmentation Through the Gene

Overview

Journal Bone Rep

Date 2024 Mar 11

PMID 38463381

Authors

Qiming Xu

Lijia Cui

Yude Lin

Leigh-Anne Cui

Weibo Xia

Affiliations

Soon will be listed here.

Abstract

Filamin B (FLNB) plays an important role in skeletal development. Mutations in 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 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. hybridization of embryos was performed to examine the transcription of genes during embryonic development. The expression of was downregulated in and mice, compared to mice. Fusions in tarsal bones were found in and mice, indicating that the skeletal segmentation was interfered with. In the embryo of mice (E12.5), the transcription levels of and were downregulated in the carpal region and cervical spine region, respectively. This study indicated that the loss-of-function mutation G1586R in may lead to abnormal skeletal segmentation, and the mechanism was possibly associated with the downregulation of gene transcription during the embryonic period.

References

Maroteaux P, Spranger J, Stanescu V, Le Marec B, Pfeiffer R, Beighton P . Atelosteogenesis. Am J Med Genet. 1982; 13(1):15-25. DOI: 10.1002/ajmg.1320130106. View

Ferrai C, Naum-Ongania G, Longobardi E, Palazzolo M, Disanza A, Diaz V . Induction of HoxB transcription by retinoic acid requires actin polymerization. Mol Biol Cell. 2009; 20(15):3543-51. PMC: 2719572. DOI: 10.1091/mbc.e09-02-0114. View

Zheng L, Baek H, Karsenty G, Justice M . Filamin B represses chondrocyte hypertrophy in a Runx2/Smad3-dependent manner. J Cell Biol. 2007; 178(1):121-8. PMC: 2064428. DOI: 10.1083/jcb.200703113. View

Tenconi R, Kozlowski K, Largaiolli G . Boomerang dysplasia. A new form of neonatal death dwarfism. Rofo. 1983; 138(3):378-80. View

Lu J, Lian G, Lenkinski R, De Grand A, Vaid R, Bryce T . Filamin B mutations cause chondrocyte defects in skeletal development. Hum Mol Genet. 2007; 16(14):1661-75. DOI: 10.1093/hmg/ddm114. View

Kozlowski K, Tsuruta T, Kameda Y, Kan A, Leslie G . New forms of neonatal death dwarfism. Report of 3 cases. Pediatr Radiol. 1981; 10(3):155-60. DOI: 10.1007/BF00975190. View

Stanley C, Thelin J, Miles J . Mixed hearing loss in Larsen syndrome. Clin Genet. 1988; 33(5):395-8. DOI: 10.1111/j.1399-0004.1988.tb03468.x. View

Stossel T, Condeelis J, Cooley L, Hartwig J, Noegel A, Schleicher M . Filamins as integrators of cell mechanics and signalling. Nat Rev Mol Cell Biol. 2001; 2(2):138-45. DOI: 10.1038/35052082. View

Sawyer G, Clark A, Robertson S, Sutherland-Smith A . Disease-associated substitutions in the filamin B actin binding domain confer enhanced actin binding affinity in the absence of major structural disturbance: Insights from the crystal structures of filamin B actin binding domains. J Mol Biol. 2009; 390(5):1030-47. DOI: 10.1016/j.jmb.2009.06.009. View

10.

Xu Q, Wu N, Cui L, Lin M, Kumar D, George Priya Doss C . Comparative analysis of the two extremes of -mutated autosomal dominant disease spectrum: from clinical phenotypes to cellular and molecular findings. Am J Transl Res. 2018; 10(5):1400-1412. PMC: 5992551. View

11.

Quinonez S, Innis J . Human HOX gene disorders. Mol Genet Metab. 2013; 111(1):4-15. DOI: 10.1016/j.ymgme.2013.10.012. View

12.

Farrington-Rock C, Kirilova V, Dillard-Telm L, Borowsky A, Chalk S, Rock M . Disruption of the Flnb gene in mice phenocopies the human disease spondylocarpotarsal synostosis syndrome. Hum Mol Genet. 2007; 17(5):631-41. PMC: 2680151. DOI: 10.1093/hmg/ddm188. View

13.

Daniel P, Morgan T, Alanay Y, Bijlsma E, Cho T, Cole T . Disease-associated mutations in the actin-binding domain of filamin B cause cytoplasmic focal accumulations correlating with disease severity. Hum Mutat. 2011; 33(4):665-73. DOI: 10.1002/humu.22012. View

14.

Jeon G, Lee M, Jung J, Hong S, Kim Y, Sin J . Identification of a de novo heterozygous missense FLNB mutation in lethal atelosteogenesis type I by exome sequencing. Ann Lab Med. 2014; 34(2):134-8. PMC: 3948826. DOI: 10.3343/alm.2014.34.2.134. View

15.

Zhou X, Tian F, Sandzen J, Cao R, Flaberg E, Szekely L . Filamin B deficiency in mice results in skeletal malformations and impaired microvascular development. Proc Natl Acad Sci U S A. 2007; 104(10):3919-24. PMC: 1820684. DOI: 10.1073/pnas.0608360104. View

16.

Krakow D, Robertson S, King L, Morgan T, Sebald E, Bertolotto C . Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis. Nat Genet. 2004; 36(4):405-10. DOI: 10.1038/ng1319. View

17.

Kozlowski K, Sillence D, Osborn R . Boomerang dysplasia. Br J Radiol. 1985; 58(688):369-71. DOI: 10.1259/0007-1285-58-688-369. View

18.

Zhao Y, Shapiro S, Eto M . F-actin clustering and cell dysmotility induced by the pathological W148R missense mutation of filamin B at the actin-binding domain. Am J Physiol Cell Physiol. 2015; 310(1):C89-98. PMC: 4698447. DOI: 10.1152/ajpcell.00274.2015. View

19.

Larsen L, SCHOTTSTAEDT E, BOST F . Multiple congenital dislocations associated with characteristic facial abnormality. J Pediatr. 1950; 37(4):574-81. DOI: 10.1016/s0022-3476(50)80268-8. View

20.

Xu Q, Wu N, Cui L, Wu Z, Qiu G . Filamin B: The next hotspot in skeletal research?. J Genet Genomics. 2017; 44(7):335-342. DOI: 10.1016/j.jgg.2017.04.007. View