Universität zu Köln

Kaczmarek, Alexander Tobias, Bender, Daniel, Gehling, Titus, Kohl, Joshua Benedict, Daimagueler, Hulya-Sevcan, Santamaria-Araujo, Jose Angel, Liebau, Max Christoph, Koy, Anne, Cirak, Sebahattin and Schwarz, Guenter ORCID: 0000-0002-2118-9338 (2022). A defect in molybdenum cofactor binding causes an attenuated form of sulfite oxidase deficiency. J. Inherit. Metab. Dis., 45 (2). S. 169 - 183. HOBOKEN: WILEY. ISSN 1573-2665

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Kaczmarek, Alexander Tobias UNSPECIFIED UNSPECIFIED UNSPECIFIED Bender, Daniel UNSPECIFIED UNSPECIFIED UNSPECIFIED Gehling, Titus UNSPECIFIED UNSPECIFIED UNSPECIFIED Kohl, Joshua Benedict UNSPECIFIED UNSPECIFIED UNSPECIFIED Daimagueler, Hulya-Sevcan UNSPECIFIED UNSPECIFIED UNSPECIFIED Santamaria-Araujo, Jose Angel UNSPECIFIED UNSPECIFIED UNSPECIFIED Liebau, Max Christoph UNSPECIFIED UNSPECIFIED UNSPECIFIED Koy, Anne UNSPECIFIED UNSPECIFIED UNSPECIFIED Cirak, Sebahattin UNSPECIFIED UNSPECIFIED UNSPECIFIED Schwarz, Guenter UNSPECIFIED orcid.org/0000-0002-2118-9338 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-578450
DOI:	10.1002/jimd.12454
Journal or Publication Title:	J. Inherit. Metab. Dis.
Volume:	45
Number:	2
Page Range:	S. 169 - 183
Date:	2022
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1573-2665
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language INTERMEMBRANE SPACE; IMPORT; LIVER; BIOSYNTHESIS; MUTATIONS; SITE Multiple languages Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/57845