Machine learning-based identification and characterization of 15 novel pathogenic SUOX missense mutations

Kaczmarek, Alexander Tobias; Bahlmann, Nike; Thaqi, Besarta; Schwarz, Guenter

doi:10.1016/j.ymgme.2021.07.011

Cited by 7 publications

(11 citation statements)

References 40 publications

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“…The rare metabolic disorder ISOD is caused by the lack of SO activity leading to the accumulation of toxic sulfite. In various, previous studies, in vitro experiments using recombinantly expressed SO combined with structure‐guided analysis were used to elucidate the pathomechanism of SO patient variants 4,15,33 . For SO variants R366H and K379R, mild and/or attenuated cases of ISOD were reported in the literature 20,21,34 …”

Section: Discussionmentioning

confidence: 99%

“…In various, previous studies, in vitro experiments using recombinantly expressed SO combined with structureguided analysis were used to elucidate the pathomechanism of SO patient variants. 4,15,33 For SO variants R366H and K379R, mild and/or attenuated cases of ISOD were reported in the literature. 20,21,34 The affected residues promote the coordination of the Moco-phosphate within the Moco-domain of SO and a nearby residue-G362S-has been reported very recently to cause a severe form of ISOD.…”

Section: Impaired Mitochondrial Moco Insertion In So R366h Causes Los...mentioning

confidence: 99%

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A defect in molybdenum cofactor binding causes an attenuated form of sulfite oxidase deficiency

Kaczmarek

Bender

Gehling

et al. 2021

J of Inher Metab Disea

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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 À/À 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.

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Section: Discussionmentioning

confidence: 99%

Section: Impaired Mitochondrial Moco Insertion In So R366h Causes Los...mentioning

confidence: 99%

A defect in molybdenum cofactor binding causes an attenuated form of sulfite oxidase deficiency

Kaczmarek

Bender

Gehling

et al. 2021

J of Inher Metab Disea

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“…Four were identified in ISOD patients of which the G530D variant was biochemically analysed and its monomeric state was confirmed (24,25). The remaining four SOX variants found in the dimerization domain were identified among naturally occurring SUOX mutations in a machine learning approach in silico, which were proven kinetically inactive in vitro (26). These findings suggest a functional requirement of dimer formation in SOX.…”

Section: Introductionmentioning

confidence: 88%

“…The purity of the proteins was confirmed with 12 % SDS-PAGE using Coomassie-staining and the dimerization state was confirmed using analytical SEC (Superdex 200, 25 ml, GE Healthcare). Mo domain and SOX R217W were expressed and purified as previously described (18,26).…”

Section: Methodsmentioning

confidence: 99%

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Molecular mechanism of intramolecular electron transfer in dimeric sulfite oxidase

Eh¹,

Kaczmarek²,

Schwarz³

et al. 2022

Journal of Biological Chemistry

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Consensus guidelines for the diagnosis and management of isolated sulfite oxidase deficiency and molybdenum cofactor deficiencies

Schwahn,

van Spronsen,

Misko

et al. 2024

J of Inher Metab Disea

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Sulfite intoxication is the hallmark of four ultrarare disorders that are caused by impaired sulfite oxidase activity due to genetic defects in the synthesis of the molybdenum cofactor or of the apoenzyme sulfite oxidase. Delays on the diagnosis of these disorders are common and have been caused by their unspecific presentation of acute neonatal encephalopathy with high early mortality, followed by the evolution of dystonic cerebral palsy and also by the lack of easily available and reliable diagnostic tests. There is significant variation in survival and in the quality of symptomatic management of affected children. One of the four disorders, molybdenum cofactor deficiency type A (MoCD‐A) has recently become amenable to causal treatment with synthetic cPMP (fosdenopterin). The evidence base for the rational use of cPMP is very limited. This prompted the formulation of these clinical guidelines to facilitate diagnosis and support the management of patients. The guidelines were developed by experts in diagnosis and treatment of sulfite intoxication disorders. It reflects expert consensus opinion and evidence from a systematic literature search.

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Machine learning-based identification and characterization of 15 novel pathogenic SUOX missense mutations

Cited by 7 publications

References 40 publications

A defect in molybdenum cofactor binding causes an attenuated form of sulfite oxidase deficiency

A defect in molybdenum cofactor binding causes an attenuated form of sulfite oxidase deficiency

Molecular mechanism of intramolecular electron transfer in dimeric sulfite oxidase

Consensus guidelines for the diagnosis and management of isolated sulfite oxidase deficiency and molybdenum cofactor deficiencies

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