ClinVar

In a brother and sister, born of parents from neighboring valleys in northern Spain, with congenital bile acid synthesis defect-6 (CBAS6; 617308), Monte et al. (2017) identified a homozygous c.673C-T transition (c.673C-T, NM_003500) in exon 6 of the ACOX2 gene, resulting in an arg225-to-trp (R225W) substitution. The mutation, which was found by direct sequencing of the gene, was present in heterozygous state in the unaffected parents. It was found at a low frequency (0.04%) in the dbSNP database. In vitro functional expression studies in human hepatoblastoma cells showed that the mutant protein was expressed at levels comparable to wildtype and localized properly to the peroxisome, but resulted in significantly decreased production of cholic acid compared to controls. Incubation of hepatoblastoma cells with THCA caused oxidative stress and cell death in a dose-dependent manner, which could be rescued by wildtype ACOX2, but not R225W ACOX2.

In 4 patients from 2 generations of a family (case 1) and an unrelated patient (case 2) with CBAS6, Alonso-Pena et al. (2022) identified homozygosity for the R225W mutation in the ACOX2 gene. The mutation was identified by sequencing of the ACOX2 gene and segregated with disease in the families. Liver biopsies from 2 of the patients demonstrated absence of ACOX2 expression.

In 2 unrelated patients (cases 3 and 4) with CBAS6, Alonso-Pena et al. (2022) identified compound heterozygous mutations in the ACOX2 gene: R225W and a 4-bp deletion (c.456_459del; 601641.0004) resulting in a frameshift and premature termination (Thr154fs). The mutation was identified by sequencing of the ACOX2 gene and segregated with disease in the families. Liver biopsies from the 2 patients demonstrated absence of ACOX2 expression. Both patients had accumulation of C27 bile acids.