Huijmans Jan G M, Schot Rachel, de Klerk Johannis B C, Williams Monique, de Coo René F M, Duran Marinus, Verheijen Frans W, van Slegtenhorst Marjon, Mancini Grazia M S
Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands.
Department of Pediatrics, Erasmus MC Sophia, Rotterdam, The Netherlands.
Am J Med Genet A. 2017 Jun;173(6):1601-1606. doi: 10.1002/ajmg.a.38240.
We describe the clinical presentation and 17 years follow up of a boy, born to consanguineous parents and presenting with intellectual disability (ID), autism, "marfanoid" dysmorphic features, and moderate abnormalities of sulfite metabolism compatible with molybdenum cofactor deficiency, but normal sulfite oxidase activity in cultured skin fibroblasts. Genomic exome analysis revealed a homozygous MOCS3 missense mutation, leading to a p.Ala257Thr substitution in the highly conserved ubiquitin-like-domain of the protein. MOCS3 is the third protein, besides MOCS1 and MOCS2, involved in the biosynthesis of the molybdenum cofactor and has a dual ubiquitin-like function in tRNA thiolation. It is plausible that the phenotype results from deficiency of this dual function, not only from defective synthesis of molybdenum cofactor, which would explain similarities and differences from the MOCS1 and MOCS2-related disorders. This observation should encourage testing of additional ID patients with mild abnormalities of sulfite metabolism for MOCS3 mutations.
我们描述了一名男孩的临床表现及17年随访情况。该男孩父母为近亲结婚，患有智力残疾（ID）、自闭症、“类马凡氏”畸形特征，且亚硫酸盐代谢存在中度异常，符合钼辅因子缺乏症，但培养的皮肤成纤维细胞中亚硫酸盐氧化酶活性正常。基因组外显子分析发现一个纯合的MOCS3错义突变，导致该蛋白高度保守的泛素样结构域中发生p.Ala257Thr替换。MOCS3是除MOCS1和MOCS2之外，参与钼辅因子生物合成的第三种蛋白质，在tRNA硫醇化过程中具有双重泛素样功能。该表型可能是由于这种双重功能的缺乏所致，而不仅仅是由于钼辅因子合成缺陷，这可以解释与MOCS1和MOCS2相关疾病的异同。这一观察结果应促使对亚硫酸盐代谢轻度异常的其他ID患者进行MOCS3突变检测。
