ClinVar

In affected members of a family with autosomal dominant Fanconi renotubular syndrome-3 (FRTS3; 615605) originally reported by Tolaymat et al. (1992), Klootwijk et al. (2014) identified a heterozygous c.7G-A transition in exon 1 of the EHHADH gene, resulting in a glu3-to-lys (E3K) substitution at a highly conserved residue. The substitution predicted the creation of an N-terminal mitochondrial targeting motif. The mutation was found by genomewide linkage analysis followed by Sanger sequencing of candidate genes in the region. The mutation segregated with the disorder in the family, and was not present in the dbSNP (build 137) or 1000 Genomes Project databases, or in 200 control alleles. Transfection of the mutation into several cell lines, including a renal proximal tubular cell line, showed that the mutant protein localized to mitochondria as well as to peroxisomes, whereas wildtype EHHADH localized only to peroxisomes. Electron microscopy of cells with the mutation showed no mitochondrial morphologic abnormalities. However, transfected renal tubular cells showed a defect in the transepithelial transport of fluids, with an inability to maintain fluid-filled domes in confluent monolayers. Transfected cells also showed a defect in luminal to basolateral transport of a glucose surrogate. These changes were associated with a defect in mitochondrial respiration and impaired ATP production. Mutant EHHADH coimmunoprecipitated with mitochondrial HADHA (600890) and HADHB (143450), which likely impaired mitochondrial function. These findings, combined with the lack of renal or mitochondrial dysfunction in Ehhadh-null mice, were consistent with a dominant-negative toxic effect of the mutant EHHADH protein rather than haploinsufficiency.