Mitochondrial genes modulate the phenotypic expression of congenital scoliosis syndrome caused by mutations in the TBXT gene

Background Congenital scoliosis (CS) is a spinal disorder caused by genetic-congenital vertebral malformations and may be associated with other congenital defects or may occur alone. It is genetically heterogeneous and numerous genes contributing to this disease have been identified. In addition, CS has a wide range of phenotypic and genotypic variability, which has been explained by the intervention of genetic factors like modifiers and environment genes. The aim of the present study was to determine the possible cause of CS in a Tunisian patient and to examine the association between mtDNA mutations and mtDNA content and CS. Methods Here we performed Whole-Exome Sequencing (WES) in a patient presenting clinical features suggestive of severe congenital scoliosis syndrome. Direct sequencing of the whole mitochondrial DNA (mtDNA) was also performed in addition to copy number quantification in the blood of the indexed case. In silico prediction tools, 3D modeling and molecular docking approaches were used. Results The WES revealed the homozygous missense mutation c.512A > G (p.H171R) in the TBXT gene. Bioinformatic analysis demonstrated that the p.H171R variant was highly deleterious and caused the TBXT structure instability. Molecular docking revealed that the p.H171R mutation disrupted the monomer stability which seemed to be crucial for maintaining the stability of the homodimer and consequently to the destabilization of the homodimer-DNA complex. On the other hand, we hypothesized that mtDNA can be a modifier factor, so, the screening of the whole mtDNA showed a novel heteroplasmic m.10150T > A (p.M31K) variation in the MT-ND3 gene. Further, qPCR analyses of the patient’s blood excluded mtDNA depletion. Bioinformatic investigation revealed that the p.M31K mutation in the ND3 protein was highly deleterious and may cause the ND3 protein structure destabilization and could disturb the interaction between complex I subunits. Conclusion We described the possible role of mtDNA genetics on the pathogenesis of congenital scoliosis by hypothesizing that the presence of the homozygous variant in TBXT accounts for the CS phenotype in our patient and the MT-ND3 gene may act as a modifier gene.