Study on Congenital Dicarboxylic Aciduria and ABC Protein

尿中二羧酸排泄异常见于线粒体脂肪酸紊乱、过氧化物酶体紊乱等患者。这种生化异常被认为与发育障碍有关。近年来，作为ATP结合盒蛋白（ABC蛋白）超家族成员的过氧化物酶体整体膜蛋白PMP70被发现是长链二羧酸的转运体，这些二羧酸被认为在过氧化物酶体中被降解。我们研究了先天性二羧酸错误和ABC蛋白缺陷的发病机制。(1)发现ABC蛋白成员PEX1p与另一种ABC蛋白PEX6p相互作用，PEX1p是Zellweger综合征（过氧酶体生物发生障碍）的致病蛋白。(2)发现PEX6p是Zellweger综合征互补组6的致病蛋白。(3)我们发现了3例过氧化物酶体酰基辅酶a氧化酶缺乏症，其特征是长链脂肪酸积累和二羧酸尿。特征性脑MRI表现与小脑-脑干型肾上腺脑白质营养不良相似。(4)我们报道了首例PEX6p缺乏症家庭病例。父母表现出与Usher综合征相似的视觉障碍，儿童有严重的精神运动迟缓，这是过氧化物酶体生物发生障碍的典型表现。(5)明确了日本儿童肾上腺脑白质营养不良的自然病史，该疾病是由一种ABC蛋白ALD蛋白缺陷引起的。

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.