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 11 year 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.

Estrogen-Related Receptor γ Agonist DY131 Ameliorates Lipopolysaccharide-Induced Acute Liver Injury

“…For instance, liver glutathione S-transferases (GSTAs) and phenylalanine hydroxylase (PAH) were deficient upon LPS challenge and could be partially restored by DY131 (Pham et al, 2004;Richards et al, 2020). Succinyl-CoA ligase (SUCLG1), an important enzyme in TCA cycle, was also reversed by DY131 to a certain degree (Donti et al, 2016). The change of carbamoyl phosphate synthetase-1 (CPS1), a major enzyme involved in urea cycle, had a similar pattern as revealed by RNA-Seq (Park et al, 2019).…”

Contribution of nuclear and mitochondrial gene mutations in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome

“…SUCLG2 encodes a GTP-specific beta subunit of succinate-CoA ligase (SUCL), an important enzyme in TCA cycle, and primarily expressed in liver [ 47 ]. Homozygous knockout model of SUCLG2 in mice showed recessive lethality [ 48 ].…”

“…Homozygous knockout model of SUCLG2 in mice showed recessive lethality [ 48 ]. Patients with SUCL deficiency showed mtDNA depletion, impaired respiratory complex subunits and mitochondrial encephalomyopathy [ 47 – 49 ]. Mutation in SUCLG2 has not been reported so far in any patients with mitochondrial disorder.…”

Phenotypic variability in deficiency of the α subunit of succinate‐CoA ligase

“…2 Further patient reports demonstrate a range of phenotypic expression in SUCLG1 deficiency. 3 A recent report describes two siblings who died at 29 and 31 months due to a homozygous mutation in the SUCLG1 protein mitochondrial targeting sequence. 4 The SUCLA2 deficiency has been a relatively less severe disorder characterized by a Leigh-like encephalomyopathy with psychomotor retardation, poor growth, neurosensory deafness, and dystonia.…”

“…There are few genotype-phenotype relationships reported and only two descriptions of Krebs cycle enzyme activity in patients with SUCLG1 gene defects. 3,4,11,12 To further characterize the SUCLG1 gene defect in our patient, we developed an liquid chromatography tandem mass spectrometry (LC-MS/MS)-based enzyme assay to verify that the hypomorphic mutations were indeed pathogenic. 13…”