학술논문
A defect in molybdenum cofactor binding causes an attenuated form of sulfite oxidase deficiency.
Document Type
Academic Journal
Author
Kaczmarek AT; Department of Chemistry, Institute of Biochemistry, University of Cologne, Cologne, Germany.; Centre for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.; Bender D; Department of Chemistry, Institute of Biochemistry, University of Cologne, Cologne, Germany.; Department of Pediatric Neurology, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland.; Gehling T; Department of Chemistry, Institute of Biochemistry, University of Cologne, Cologne, Germany.; Kohl JB; Department of Chemistry, Institute of Biochemistry, University of Cologne, Cologne, Germany.; Daimagüler HS; Centre for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.; Department of Pediatrics, University Hospital Cologne and Faculty of Medicine, University of Cologne, Cologne, Germany.; Santamaria-Araujo JA; Department of Chemistry, Institute of Biochemistry, University of Cologne, Cologne, Germany.; Liebau MC; Centre for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.; Department of Pediatrics, University Hospital Cologne and Faculty of Medicine, University of Cologne, Cologne, Germany.; Koy A; Department of Pediatrics, University Hospital Cologne and Faculty of Medicine, University of Cologne, Cologne, Germany.; Cirak S; Centre for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.; Department of Pediatrics, University Hospital Cologne and Faculty of Medicine, University of Cologne, Cologne, Germany.; Schwarz G; Department of Chemistry, Institute of Biochemistry, University of Cologne, Cologne, Germany.; Centre for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
Source
Publisher: Wiley Country of Publication: United States NLM ID: 7910918 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1573-2665 (Electronic) Linking ISSN: 01418955 NLM ISO Abbreviation: J Inherit Metab Dis Subsets: MEDLINE
Subject
Language
English
Abstract
Isolated sulfite oxidase deficiency (ISOD) is a rare recessive and infantile lethal metabolic disorder, which is caused by functional loss of sulfite oxidase (SO) due to mutations of the SUOX gene. SO is a mitochondrially localized molybdenum cofactor (Moco)- and heme-dependent enzyme, which catalyzes the vital oxidation of toxic sulfite to sulfate. Accumulation of sulfite and sulfite-related metabolites such as S-sulfocysteine (SSC) are drivers of severe neurodegeneration leading to early childhood death in the majority of ISOD patients. Full functionality of SO is dependent on correct insertion of the heme cofactor and Moco, which is controlled by a highly orchestrated maturation process. This maturation involves the translation in the cytosol, import into the intermembrane space (IMS) of mitochondria, cleavage of the mitochondrial targeting sequence, and insertion of both cofactors. Moco insertion has proven as the crucial step in this maturation process, which enables the correct folding of the homodimer and traps SO in the IMS. Here, we report on a novel ISOD patient presented at 17 months of age carrying the homozygous mutation NM_001032386.2 (SUOX):c.1097G > A, which results in the expression of SO variant R366H. Our studies show that histidine substitution of Arg366, which is involved in coordination of the Moco-phosphate, causes a severe reduction in Moco insertion efficacy in vitro and in vivo. Expression of R366H in HEK SUOX -/- cells mimics the phenotype of patient's fibroblasts, representing a loss of SO expression and specific activity. Our studies disclose a general paradigm for a kinetic defect in Moco insertion into SO caused by residues involved in Moco coordination resulting in the case of R366H in an attenuated form of ISOD.
(© 2021 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)
(© 2021 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)