CHARACTERIZATION OF MISSENSE MUTATIONS AND BIOCHEMICAL ANALYSIS OF INCREASED LIPID PEROXIDATION AND MITOCHONDRIAL DYSFUNCTION IN ACERULOPLASMINEMIA

铜浆蛋白血症中脂质过氧化增加和线粒体功能障碍的错义突变特征和生化分析

• 批准号: 12670600
• 负责人: MIYAJIMA Hiroaki
• 金额: $ 1.98万
• 依托单位: HAMAMATSU UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670600/
• 关键词: CERULOPLASMIN; MISSENSE MUTATION; IRON; LIPID PEROXIDATION; MITOCHONDRIA; FREE RADICAL; FERROXIDASE; SECRETORY PATHWAY; 銅; 小胞体ストレス; 銅抱合能; エネルギー産生系; 遺伝子発現; 小胞体; タエロオキシダーゼ; フェロオキシダーゼ; 神経変性症

Aceruloplasminemia, an autosomal recessive disorder that affects iron metabolism, is caused by mutations of the ceruloplasmin gene. It is characterized by iron accumulation in the brain as well as visceral organs. Clinically, the disease consists of the triad of retinal degeneration, diabetes mellitus, and neurologic disease. Almost all the mutations in the ceruloplasmin gene reported previously were truncation mutations. To elucidate the molecular pathogenesis of aceruloplasminemia, the ceruloplasmin biosynthesis of two missense mutants was examined. A P177R mutation results in the location of ceruloplasmin within the endoplasmic reticulum as apoprotein. An H978Q mutation results in detectable serum ceruloplasmin devoid of ferroxidase activity associated with decreased copper incorporation.The unique involvement of the central nervous system distinguishes aceruloplasminemia from other inherited and acquired iron storage disorders. Excess iron functions as a potent catalyst of biologic oxidation. We showed that an increased iron concentration is associated with increased lipid peroxidation in the brains of three aceruloplasminemia patients. Positron emission tomography showed cortical glucose and oxygen hypometabolism. Enzyme activities in the mitochondrial respiratory chain of the basal ganglia were reduced to about 50% and 43% respectively for complexes I and IV. Those of the cerebral and cerebellar cortices also were decreased approximately 62% and 65%. These findings suggest that iron-mediated free radicals may contribute to increased lipid peroxidation and the impairment of mitochondrial energy metabolism in aceruloplasminemia brains.

铜蓝蛋白血症是一种影响铁代谢的常染色体隐性遗传病，由铜蓝蛋白基因突变引起。它的特点是铁在大脑和内脏器官中积累。临床上，该病由视网膜变性、糖尿病和神经系统疾病三部分组成。以前报道的铜蓝蛋白基因突变几乎都是截断突变。为了阐明无蓝蛋白血症的分子发病机制，检测了两个错义突变体的铜蓝蛋白生物合成。P177R突变导致铜蓝蛋白作为脱辅基蛋白定位于内质网中。H978Q突变导致可检测到的血清铜蓝蛋白缺乏与铜结合减少相关的铁氧合酶活性。中枢神经系统的独特参与使无蓝蛋白血症与其他遗传性和获得性铁储存疾病区分开来。过量的铁是生物氧化的有力催化剂。我们发现，铁浓度的增加与三名无纤维蛋白溶酶血症患者大脑中的脂质过氧化反应增加有关。正电子发射断层扫描显示皮质葡萄糖和氧代谢低下。络合物I和IV使基底节线粒体呼吸链的酶活性分别降低约50%和43%，大脑皮层和小脑皮质的酶活性分别降低约62%和65%。这些发现提示，铁介导的自由基可能有助于无浆蛋白血症脑内脂质过氧化和线粒体能量代谢障碍的增加。

项目成果

Miyajima H.: "Increased oxysterols associated with iron accumulation in the brains and visceral organe of acerulovlasmineuia"Q. J. Med.. 94・8. 417-422 (2001)

Miyajima H.：“与 acerulovlasmineuia 的大脑和内脏器官中铁积累相关的氧化甾醇增加”Q. J. Med.. 94・8 (2001)。

Hellman N.E.: "Biochemical analysis of a missense mutation in aceruloplasminemia"J Biol Chem. 277. 1375-1380 (2002)

Hellman N.E.：“铜蓝蛋白血症错义突变的生化分析”J Biol Chem。

Kaneko K.: "Astrocytic deformity and globular structures are characteristic of The brains of patients with aceruloplasminemia"J Neuropathol Exp Neurol. 61・12. 1069-1077 (2002)

Kaneko K.：“星形细胞畸形和球状结构是铜蓝蛋白血症患者大脑的特征”J Neuropathol Exp Neurol 61・1077（2002）。

Miyajima H.: "Glucose and oxygen hypometabolism in a aceruloplasminemia brains"Int Med. 41・3. 186-190 (2002)

Miyajima H.：“无铜蓝蛋白血症脑中的葡萄糖和氧代谢低下”Int Med 41・3（2002）。

Miyajima H: "Aceruloplasminemia, an inherited disorder of iron metabolism"Biometals. 16(1). 205-213 (2003)

Miyajima H：“铜蓝蛋白血症，一种铁代谢的遗传性疾病”Biometals。