Rare loss-of-function variants in <i>FLNB</i> cause non-syndromic orofacial clefts

Wenbin Huang; Shiying Zhang; Jiuxiang Lin; Yi Ding; Nan Jiang; Jieni Zhang; Huaxiang Zhao; Feng Chen

doi:10.1016/j.jgg.2023.03.012

Volume 51 Issue 2

Feb. 2024

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Article Navigation > Journal of Genetics and Genomics > 2024 > 51(2): 222-229

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Rare loss-of-function variants in FLNB cause non-syndromic orofacial clefts

doi: 10.1016/j.jgg.2023.03.012

a. Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing, 100081, China;
b. Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi, 710004, China;
c. Guangdong Provincial High-level Clinical Key Specialty, Guangdong Province Engineering Research Center of Oral Disease Diagnosis and Treatment, Department of Orthodontics, Stomatological Center, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, Guangdong 518036, China;
d. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, 710049, China;
e. National Center for Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory for Digital Stomatology, Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health, NMPA Key Laboratory for Dental Materials, Beijing, 100101, China;
f. Central Laboratory, Peking University School and Hospital of Stomatology, Beijing, 100081, China

Funds:

The authors would like to thank all the participants involved in this study. This work is a part of a series of studies focusing on orofacial clefts under the supervision of Prof. Jiuxiang Lin. This work was supported by the National Natural Science Foundation of China (No. 81870747, 82170916, 81900984, and 82001030), the Fundamental Research Funds for the Central Universities (PKU2022XGK001), Natural Science Foundation of Beijing Municipality (7182184), Xi'an “Science and Technology+” Action Plan-Medical Research Project (20YXYJ0010[1]), and the Fundamental Research Funds for the Central Universities (xzy012020110).

Received Date: 2022-12-21
Accepted Date: 2023-03-17
Rev Recd Date: 2023-02-24
Publish Date: 2023-03-31

Abstract

Abstract

Orofacial clefts (OFCs) are the most common congenital craniofacial disorders, of which the etiology is closely related to rare coding variants. Filamin B (FLNB) is an actin-binding protein implicated in bone formation. FLNB mutations have been identified in several types of syndromic OFCs and previous studies suggest a role of FLNB in the onset of non-syndromic OFCs (NSOFCs). Here, we report two rare heterozygous variants (p.P441T and p.G565R) in FLNB in two unrelated hereditary families with NSOFCs. Bioinformatics analysis suggests that both variants may disrupt the function of FLNB. In mammalian cells, p.P441T and p.G565R variants are less potent to induce cell stretches than wild type FLNB, suggesting that they are loss-of-function mutations. Immunohistochemistry analysis demonstrates that FLNB is abundantly expressed during palatal development. Importantly, Flnb^−/− embryos display cleft palates and previously defined skeletal defects. Taken together, our findings reveal that FLNB is required for development of palates in mice and FLNB is a bona fide causal gene for NSOFCs in humans.
- Orofacial clefts,
- FLNB,
- Loss-of-function mutation,
- Cleft palate,
- Filamin B,
- Actin filament,
- Knockout mouse

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References(32)

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