Mutations in COQ8B found in patients with steroid-resistant nephrotic syndrome Alter COQ8B function

Resumen del póster presentado a la XI Reunión Anual CIBERER, celebrada en Castelldefels, Barcelona del 12 al 14 de marzo de 2018.
The coenzyme Q (CoQ) biosynthesis pathway has been well studied in yeast and comprises at least 12 COQ genes. COQ8 encodes an atypical protein kinase that appears to be essential for the phosphorylation of several Coq polypeptides. Yeast COQ8 mutants lack CoQ and are not able to growth in non-fermentable carbon media sources as glycerol. Humans harbor two paralog genes of COQ8; COQ8A and COQ8B (previously termed ADCK3 and ADCK4). Mutations in COQ8B cause steroid-resistant nephrotic syndrome with variable neurological involvement. We have found that COQ8B is a mitochondrial matrix protein peripherally associated with the inner membrane with a similar behavior to other COQ proteins like COQ4 and COQ5. Moreover, COQ8B can complement a COQ8 yeast null strain when its mitochondrial targeting sequence (MTS) is replaced by either the yCOQ3 or yCOQ8 MTS, but not when the MTS was simply added to the N-terminus. This model was employed to validate COQ8B mutations, and to establish genotype–phenotype correlations. All mutations affected respiratory growth, but there was no correlation between mutation type and the severity of the phenotype. These data also suggest that the system is redundant, and that other proteins (probably COQ8A) may partially compensate for the absence of COQ8B. Finally, a COQ8B polymorphism, present in 50% of the European population (NM_024876.3:c.521A > G, p.His174Arg), affects stability of the protein and could represent a risk factor for secondary CoQ deficiencies.