Loss of function NOG variant causes radiounlar synostosis

Abstract Background: Several NOG variants have been reported in patients with congenital joint fusion syndromes. Radioulnar synostosis (RUS) is the most common joint malformation of upper limbs. This study aims to explore NOG mutations in RUS. Methods : Exome and Sanger sequencing data were used to identify NOG variants in 325 patients with RUS. Parental relationship was determined by STR mapping. Pathogenicity was evaluated for variants with interest. HeLa and U-2OS cells were cultured in vitro with the transfection of flag-tagged NOG -WT, NOG -Q221X, and control clones. Gene expression, protein levels, and cellular localization were determined using RT-PCR, Western blot analysis, and immunofluorescence. Results : A de novo NOG variant, i.e., c .661C>T/p.Q221X, was identified on a patient with RUS. Compared with WT, c.661C>T/p.Q221X showed a significantly decreased mRNA expression in HeLa and U-2OS cells transfected with the plasmids. In mutant status, the NOG protein was undetectable in Western blot assay. Cell immunofluorescence confirmed that the Q221X mutant protein was undetectable. Conclusion: This study confirmed that mutant NOG is a rare cause of human RUS. Patients with RUS in clinic should be evaluated for NOG variants.