The first Korean cases of combined oxidative phosphorylation deficiency 35 with two novel TRIT1 mutations in two siblings confirmed by clinical and molecular investigation

Abstract

Background: Combined oxidative phosphorylation deficiency 35 (COXPD 35) is a very rare autosomal recessive disorder caused by homozygous or compound heterozygous mutations in the TRIT1 gene on chromosome 1p34. Only six cases of COXPD 35 and six allelic variants of TRIT1 gene mutations have been reported worldwide.

Case description: We describe two siblings who presented with similar clinical features including severe intellectual disability and epilepsy with onset of symptom in early infancy.

Results: The whole exome sequencing results revealed a compound heterozygous novel variant, c.979G > A (p.Glu327Lys) and c.682 + 2 T > C, on TRIT1 exon 8 and intron 5, respectively, which was confirmed by Sanger sequencing. Protein structure analysis revealed that the p.Glu327Lys variant disrupts the conformation and electrostatic charge of the zinc-finger motif in the tRNA isopentenyltransferase (IPT), impairing binding of the mutant IPT to specific DNA sequences.

Conclusion: This is the first report of two Korean siblings with COXPD 35 with two novel variants in TRIT1. This study will help to understand the various phenotypic spectra in patients with COXPD 35 and to expand knowledge on the mechanisms of the disease based on genetic features.

Keywords: Combined oxidative phosphorylation deficiency; Epilepsy; Intellectual disability; TRIT1.