1. A missense mutation in the gene encoding the enzyme, EHHADH was identified in all members of a family diagnosed with isolated Fanconi’s syndrome (dysfunction of renal proximal tubular cells).
2. This mutation was responsible for the mistargeting of peroxisomal EHHADH, resulting in mitochondrial dysfunction.
Study Rundown: The proximal tubule is a highly metabolically active segment of the nephron; dysfunction of this segment (such as in renal Fanconi’s syndrome) may cause life-threatening metabolic abnormalities and loss of nutrients. Fanconi’s syndrome can be “acquired” whereby systemic disease results in direct proximal tubular damage or, in rare cases, “isolated” in which the pathogenesis remains unknown. Mitochondrial dysfunction has been a proposed mechanism for isolated Fanconi’s syndrome since the proximal tubule is known to be a metabolically active area.
Using gene sequencing of a family with isolated Fanconi’s syndrome as well as mouse models and biochemical studies, this study was the first to demonstrate that a single missense mutation (located on chromosome 3q27) leads to a structural change in the protein EHHADH, which normally localizes to peroxisomes. Mutated EHHADH was then shown to incorrectly bind to mitochondrial targets (HADHA and HADHB), leading to impaired cellular respiration and subsequent dysfunction of proximal tubular cells.
A limitation of this study includes the applicability of the results (i.e. molecular targets) as all human participants for the genome study were from the same family with known isolated Fanconi’s syndrome. However, as technology improves and with our advancing knowledge in pathogenesis of specific conditions, the wider implication of this study is the possibility for molecular screening in the future as more targets continue to be elucidated.
In-Depth: Eighteen members of one black family (nine members with Fanconi’s syndrome) were enrolled into the study. Genomewide linkage analysis and gene sequencing identified a single heterozygous missense mutation in EHHADH which occurred in all affected family members. Urine metabolite analysis also demonstrated a unique profile when comparing Fanconi’s versus non-Fanconi’s syndrome family members. Cell-based studies (transfection of model proximal tubular cells with normal versus mutant EHHADH) demonstrated mutant EHHADH localization to mitochondria and a defect in the transepithelial transport of fluids – both of which were not seen in cells with normal EHHADH. Measurement of mitochondrial respiratory function also confirmed reduced energy production in mutant EHHADH transfected cells. Finally, complete knockout of EHHADH in mice had no significant effect on urinary electrolyte excretion or metabolites, indicating that mistargeting of mutant EHHADH to mitochondria is the pathogenetic mechanism.
By Jonathan Liu, MD and Adrienne Cheung
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