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Cryptophthalmos, dental anomalies, oral vestibule defect, and a novel FREM2 mutation



FREM2 is a member of the FREM2–FRAS1–FREM1 protein complex which contributes to epithelial–mesenchymal coupling. We report a Thai woman with cryptophthalmos, dental anomalies, and oral vestibule defect. A compound heterozygous mutation (c.6499C>T; p.Arg2167Trp and c.641_642del; p.Glu214GlyfsTer135) in the FREM2 gene was identified. The frameshift variant p.Glu214GlyfsTer135 is de novo and novel. It is predicted to result in the loss of most of the functional domains. The p.Arg2167Trp mutation was predicted to disrupt both Ca2+ binding and conformational change. The Arg2167Trp mutant protein has been shown to cause partial loss of function, decrease its interaction with FREM1 and result in impaired function of the FRAS1–FREM2–FREM1 complex. Frem2 was shown to be expressed in the developing tooth and vestibular lamina. It is hypothesized that these mutations resulted in aberration of the FRAS1–FREM2–FREM1 protein complex, resulting in loss of nephronectin, basement membrane disruption, and abnormal epithelial–mesenchymal interactions leading to dental and oral vestibule malformations.

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We thank our patient and her families for their kind cooperation and for allowing us to use their medical and dental information for the benefit of others. This work was supported by the Thailand Research Fund (BRG6180007) and Genomics Thailand Research Grant of Health System Research Institute (HSRI) of Thailand.

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Correspondence to Piranit Nik Kantaputra.

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Kantaputra, P.N., Wangtiraumnuay, N., Ngamphiw, C. et al. Cryptophthalmos, dental anomalies, oral vestibule defect, and a novel FREM2 mutation. J Hum Genet (2021).

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