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One of the recent report indicated that a severe patient of MDMDs carries the NP_056528.2:p.Asn221Ser (N221S) variation in the RRM2B gene (NM_015713.5). However, there is no direct evidence demonstrating the nature of the N221S variation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and Methods<\/jats:title><jats:p>This study aimed to utilize zebrafish and morpholino oligomer (MO) knockdown technique to provide direct evidence for the nature of the N221S variation in the RRM2B.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The results showed that two distinct MOs were both able to perturb the expression of <jats:italic>rrm2b<\/jats:italic> in zebrafish and dose\u2010dependently induced morphological defects. Furthermore, co\u2010injection of human wild\u2010type <jats:italic>RRM2B<\/jats:italic> mRNA with MO\u2010e4i4 successfully rescued the developmental defects, whereas co\u2010injection of <jats:italic>RRM2B<\/jats:italic>\/<jats:italic>N221S<\/jats:italic> mRNA with MO\u2010e4i4 did not rescue the developmental defects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In conclusion, the functional assay in this study provided the direct evidence proving that the N221S variation is a loss\u2010of\u2010function mutation and plausibly related to the pathogenic developmental defects found in the infants of previous clinical reports.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.1497","type":"journal-article","created":{"date-parts":[[2020,11,16]],"date-time":"2020-11-16T06:35:26Z","timestamp":1605508526000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The single nucleotide variant at 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