Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease

J Inherit Metab Dis. 2020 Sep;43(5):1024-1036. doi: 10.1002/jimd.12232.

Marisa W Friederich ¹ ², Abdallah F Elias ³, Alice Kuster ⁴ ⁵, Lucia Laugwitz ⁶, Austin A Larson ¹, Aaron P Landry ⁷, Logan Ellwood-Digel ¹, David M Mirsky ⁸, David Dimmock ⁹, Jaclyn Haven ³, Hua Jiang ¹, Kenneth N MacLean ¹, Katie Styren ³, Jonathan Schoof ³, Louise Goujon ⁴ ¹⁰, Thomas Lefrancois ¹¹, Maike Friederich ¹, Curtis R Coughlin 2nd ¹, Ruma Banerjee ⁷, Tobias B Haack ⁵ ¹², Johan L K Van Hove ¹ ²

Affiliations

1 Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Aurora, Colorado.
2 Department of Pathology and Laboratory Medicine, Children's Hospital Colorado, Aurora, Colorado.
3 Department of Medical Genetics, Shodair Children's Hospital, Helena, Montana.
4 Department of Neurometabolism, University Hospital of Nantes, Nantes, France.
5 INRAE, UMR1280, PhAN, Nantes Université, Nantes, France.
6 Institut für Medizinische Genetik und Angewandte Genomik, Universitätsklinikum, University of Tübingen, Tübingen, Germany.
7 Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan.
8 Department of Radiology, University of Colorado, and Children's Hospital Colorado, Aurora, Colorado.
9 Rady Children's Institute for Genomic Medicine, San Diego, California.
10 Service de Génétique Clinique, University Hospital of Rennes, Rennes, France.
11 Pediatric Radiology, University Hospital of Nantes, Nantes, France.
12 Centre for Rare Diseases, University of Tübingen, Tübingen, Germany.

PMID: 32160317 DOI: 10.1002/jimd.12232

Abstract

Hydrogen sulfide, a signaling molecule formed mainly from cysteine, is catabolized by sulfide:quinone oxidoreductase (gene SQOR). Toxic hydrogen sulfide exposure inhibits complex IV. We describe children of two families with pathogenic variants in SQOR. Exome Sequencing identified variants; SQOR Enzyme activity was measured spectrophotometrically, protein levels evaluated by western blotting, and mitochondrial function was assayed. In family A, following a brief illness, a 4-year-old girl presented comatose with lactic acidosis and multiorgan failure. After stabilization, she remained comatose, hypotonic, had neurostorming episodes, elevated lactate, and Leigh-like lesions on brain imaging. She died shortly after. Her 8-year-old sister presented with a rapidly fatal episode of coma with lactic acidosis, and lesions in the basal ganglia and left cortex. Muscle and liver tissue had isolated decreased complex IV activity, but normal complex IV protein levels and complex formation. Both patients were homozygous for c.637G > A, which we identified as a founder mutation in the Lehrerleut Hutterite with a carrier frequency of 1 in 13. The resulting p.Glu213Lys change disrupts hydrogen bonding with neighboring residues, resulting in severely reduced SQOR protein and Enzyme activity, whereas sulfide generating Enzyme levels were unchanged. In family B, a boy had episodes of encephalopathy and basal ganglia lesions. He was homozygous for c.446delT and had severely reduced fibroblast SQOR Enzyme activity and protein levels. SQOR dysfunction can result in hydrogen sulfide accumulation, which, consistent with its known toxicity, inhibits complex IV resulting in energy failure. In conclusion, SQOR deficiency represents a new, potentially treatable, cause of Leigh disease.

Keywords

Leigh disease; complex IV; hydrogen sulfide; sulfide:quinone oxidoreductase; treatment.

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