Study on Congenital Dicarboxylic Aciduria and ABC Protein

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Abnormal excretion of dicarboxylic acids in urine is found in patients with mitochondrial fatty acid disorders, peroxisomal disorders and others. This biochemical abnormality is considered to relate to developmental disorders. Recently, a peroxisomal integral membrane protein PMP70 which is a member of ATP binding cassette protein (ABC protein) superfamily, was found to be a transporter of long chain dicarboxylic acids, and these dicarboxylic acids are considered to be degraded in peroxisomes. We investigated pathogenesis of inborn errors of dicarboxylic acid and defects of ABC proteins.(1) PEX1p, a member of ABC protein and a pathogenic protein of Zellweger syndrome (peroxisome biogenesis disorders) , was found to interact with PEX6p, an another ABC protein and a pathogenic protein of Zellweger syndrome.(2) PEX6p was found to be a pathogenic protein of complementation group 6 of Zellweger syndrome.(3) We identified 3 patients with peroxisomal acyl-CoA oxidase deficiency which was characterized by accumulation of very-long chain fatty acids and dicarboxylic aciduria. Characteristic brain MRI findings were similar to those of cerebello-brainstem type of adrenoleukodystrophy.(4) We reported the first family cases of PEX6p deficiency. Parents manifested visual disturbance which was similar to Usher syndrome, and the child suffered severe psychomotor retardation typical for peroxisome biogenesis disorders.(5) Natural history of Japanese children with adrenoleukodystrophy which is caused by a defect in ALD protein, an ABC protein, was clarified.