title: Expanding the phenotypic spectrum of Succinyl-CoA ligase deficiency through functional validation of a new SUCLG1 variant.
abstract: Deficiency of the TCA cycle enzyme Succinyl-CoA Synthetase/Ligase (SCS), due to pathogenic variants in subunits encoded by SUCLG1 and SUCLA2, causes mitochondrial encephalomyopathy, methylmalonic acidemia, and mitochondrial DNA (mtDNA) depletion. In this study, we report an 11year old patient who presented with truncal ataxia, chorea, hypotonia, bilateral sensorineural hearing loss and preserved cognition. Whole exome sequencing identified a heterozygous known pathogenic variant and a heterozygous novel missense variant of uncertain clinical significance (VUS) in SUCLG1. To validate the suspected pathogenicity of the novel VUS, molecular and biochemical analyses were performed using primary skin fibroblasts from the patient. The patient's cells lack the SUCLG1 protein, with significantly reduced levels of SUCLA2 and SUCLG2 protein. This leads to essentially undetectable SCS enzyme activity, mtDNA depletion, and cellular respiration defects. These abnormal phenotypes are rescued upon ectopic expression of wild-type SUCLG1 in the patient's fibroblasts, thus functionally confirming the pathogenic nature of the SUCLG1 VUS identified in this patient and expanding the phenotypic spectrum for SUCLG1 deficiency.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Taraka R
authors.initials: TR
authors.lastname: Donti
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Ruchi
authors.initials: R
authors.lastname: Masand
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Daryl A
authors.initials: DA
authors.lastname: Scott
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Craigen
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Electronic address: bgraham@bcm.edu.
authors.forename: Brett H
authors.initials: BH
authors.lastname: Graham
mesh_terms: D000214:Acyl Coenzyme A / Q000235:genetics / Q000378:metabolism; D000592:Amino Acid Metabolism, Inborn Errors / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D002648:Child; D004272:DNA, Mitochondrial / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D013389:Succinate-CoA Ligases / Q000235:genetics* / Q000378:metabolism; D000073359:Exome Sequencing
chemical_list: D000214:Acyl Coenzyme A; D004272:DNA, Mitochondrial; C012046:succinyl-coenzyme A; C000611245:SUCLG1 protein, human; D013389:Succinate-CoA Ligases; C518788:SUCLA2 protein, human
keywords: Methylmalonic aciduria; Mitochondria; Mitochondrial DNA depletion; Succinyl-CoA synthetase; TCA cycle