Mutations in COQ8B (ADCK4) found in patients with steroid-resistant nephrotic syndrome alter COQ8B function

Abstract

Mutations in COQ8B cause steroid‐resistant nephrotic syndrome with variable neurological involvement. In yeast, COQ8 encodes a protein required for coenzyme Q (CoQ) biosynthesis, whose precise role is not clear. Humans harbor two paralog genes: COQ8A and COQ8B (previously termed ADCK3 and ADCK4). We have found that COQ8B is a mitochondrial matrix protein peripherally associated with the inner membrane. COQ8B can complement a ΔCOQ8 yeast strain when its mitochondrial targeting sequence (MTS) is replaced by a yeast MTS. 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. In fact, contrary to the case of COQ2, where residual CoQ biosynthesis correlates with clinical severity, patients harboring hypomorphic COQ8B alleles did not display a different phenotype compared with those with null mutations. 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 or for other complex traits.

Functional analysis of Aarf domain‐containing kinase 1 in Drosophila melanogaster

“…6 Coq8 is part of a multiprotein complex involved in the biosynthesis of Coenzyme Q (CoQ), which is a lipid that resides in the mitochondrial inner membrane and contributes to electron transport. 12,13 In spite of multiple studies, however, the molecular functions of Coq8 and its human counterparts remain unclear. 7-10 A recent biochemical study has shown that ADCK3 can bind ATP and adopt an atypical protein kinase-like fold that is blocked by autoinhibitory domains, providing initial insights into its molecular function.…”

“…11 Mutations in ADCK4 are associated with steroid-resistant nephrotic syndrome in humans as well as reduced levels of CoQ. 12,13 In spite of multiple studies, however, the molecular functions of Coq8 and its human counterparts remain unclear. 14 In addition, ADCK2 and ADCK5 are largely uncharacterized.…”

Treatment with 2,4-Dihydroxybenzoic Acid Prevents FSGS Progression and Renal Fibrosis in Podocyte-Specific Coq6 Knockout Mice

“…Several recent in vitro and in vivo studies, including ours, have demonstrated the beneficial effect of CoQ 10 in improving the outcome of primary mitochondrial diseases due to CoQ 10 deficiency. 51,52 Because CoQ 10 requires high-dose use and is not water soluble, limiting its use in cell culture systems, we decided to examine the effect of its more soluble and hydrophilic 4-HB analogs-2,4-diHB, 3,4-diHB, and vanillic acid-on podocyte function.…”

ADCK2 Haploinsufficiency Reduces Mitochondrial Lipid Oxidation and Causes Myopathy Associated with CoQ Deficiency

“…The ADCK genes encode the aarF domain-containing mitochondrial protein kinases. Both human ADCK3 (COQ8A) and ADCK4 (COQ8B) show high homology to yeast coq8 and can rescue the growth of Δcoq8 yeast strain [16,17] by contributing to the stabilization of the CoQ biosynthesis complex [18]. ADCK3 has an unorthodox kinase function by harboring an ATPase activity [19].…”