| Autor: |
Mayr SJ; Institute of Biochemistry, Department of Chemistry, University of Cologne, Zülpicher Str. 47, 50674, Köln, Germany., Sass JO; Bioanalytics & Biochemistry, Department of Natural Science, Bonn-Rhein Sieg University of Applied Sciences, Rheinbach, Germany., Vry J; Department of Neuropediatrics and Muscle Disorders, Faculty of Medicine, Medical Center - University of Freiburg, Freiburg, Germany., Kirschner J; Department of Neuropediatrics and Muscle Disorders, Faculty of Medicine, Medical Center - University of Freiburg, Freiburg, Germany., Mader I; Faculty of Medicine, Department of Neuroradiology, University of Freiburg, Freiburg, Germany., Hövener JB; Department of Radiology, Medical Physics, Faculty of Medicine, Medical Center - University of Freiburg, University of Freiburg, Freiburg, Germany.; Section for Biomedical Imaging and MOIN CC, University Medical Center Schleswig Holstein, University of Kiel, Kiel, Germany., Reiss J; Institut für Humangenetik, Universität Göttingen, Göttingen, Germany., Santamaria-Araujo JA; Institute of Biochemistry, Department of Chemistry, University of Cologne, Zülpicher Str. 47, 50674, Köln, Germany., Schwarz G; Institute of Biochemistry, Department of Chemistry, University of Cologne, Zülpicher Str. 47, 50674, Köln, Germany. gschwarz@uni-koeln.de.; Center for Molecular Medicine Cologne), University of Cologne, Cologne, Germany. gschwarz@uni-koeln.de., Grünert SC; Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center - University of Freiburg, Mathildenstr. 1, 79106, Freiburg, Germany. sarah.gruenert@uniklinik-freiburg.de. |
| Abstrakt: |
Molybdenum cofactor deficiency is an autosomal recessive inborn error of metabolism, which results from mutations in genes involved in Moco biosynthesis. Moco serves as a cofactor of several enzymes, including sulfite oxidase. MoCD is clinically characterized by intractable seizures and severe, rapidly progressing neurodegeneration leading to death in early childhood in the majority of known cases. Here we report a patient with an unusual late disease onset and mild phenotype, characterized by a lack of seizures, normal early development, a decline triggered by febrile illness and a subsequent dystonic movement disorder. Genetic analysis revealed a homozygous c.1338delG MOCS1 mutation causing a frameshift (p.S442fs) with a premature termination of the MOCS1AB translation product at position 477 lacking the entire MOCS1B domain. Surprisingly, urine analysis detected trace amounts (1% of control) of the Moco degradation product urothione, suggesting a residual Moco synthesis in the patient, which was consistent with the mild clinical presentation. Therefore, we performed bioinformatic analysis of the patient's mutated MOCS1 transcript and found a potential Kozak-sequence downstream of the mutation site providing the possibility of an independent expression of a MOCS1B protein. Following the expression of the patient's MOCS1 cDNA in HEK293 cells we detected two proteins: a truncated MOCS1AB protein and a 22.4 kDa protein representing MOCS1B. Functional studies of both proteins confirmed activity of MOCS1B, but not of the truncated MOCS1AB. This finding demonstrates an unusual mechanism of translation re-initiation in the MOCS1 transcript, which results in trace amounts of functional MOCS1B protein being sufficient to partially protect the patient from the most severe symptoms of MoCD. |
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