GENE ANALYSIS AND LIPID PEROXIDATION ASSOCIATED WITH INCREASED IRON IN PATIENTS WITH ACERULOPLASMINEMIA

与铜浆蛋白血症患者铁增加相关的基因分析和脂质过氧化

• 批准号: 10670581
• 负责人: MIYAJIMA Hiroaki
• 金额: $ 1.28万
• 依托单位: HAMAMATU UNIVERSITY SCHOOL OF MEDECINE
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670581/
• 关键词: CERULOPLASMIN; GENE FREQUENCY; IRON; LIPID PEROXIDATION; CEREBROSPINAL FLUID; FREE RADICAL; MUTATION; TRUNCATION; 無セルロプラスミン血症; 極長鎖脂肪酸

Aceruloplasminemia is a newly recognized autosomal recessive disorder of iron metabolism resulting in neurodegeneration of the retina and basal ganglia as well as diabetes mellitus. Clinically it is recognized as a triad of diabetes, retinal degeneration and neurologic disease. This disease is characterized by mutations in the ceruloplasmin gene, the absence of serum ceruloplasmin, low serum iron concentration, and iron accumulation in the brain, liver, and other tissues.1) Iron in an important catalyst of oxyradical-mediated cellular and tissue injury. CSF from affected patients revealed a three-fold increased iron concentration which was associated with increased superoxide dismutase activity and lipid peroxidation products. These findings support the hypothesis that iron-mediated lipid peroxidation contributes to neurodegeneration in patients with aceruloplasminemia. Such measurements may have value in assessing disease progression as well as the results of iron chelation and other therapeutic interventions.2) We screened the serum ceruloplasmin concentrations of 4,990 healthy adult individuals. Subsequent sequence determination of the mutant alleles showed three mutations (one homozygote and five heterozygotes). The gene frequency was 70x/100,000. In Japan, the incidence of aceruloplasminemia was estimated to be approximately one per 2,000,000 in the case of non consanguineous marriages.3) We report a 70-year-old woman with parkinsonism and late onset diabetes mellitus who had a novel mutation in the ceruloplasmin gene. Nucleotide sequence analysis of the ceruloplasmin gene showed a single bp deletion (G : nt 2068) in exon 11. This mutation produced a frame shift, resulting in the premature termination at aa 690.

紫纤溶酶血症是一种新近发现的常染色体隐性铁代谢疾病，可导致视网膜和基底神经节的神经变性以及糖尿病。临床上，它被认为是糖尿病、视网膜变性和神经系统疾病的三位一体。这种疾病的特征是铜蓝蛋白基因突变，血清铜蓝蛋白缺失，血清铁浓度低，铁在脑、肝和其他组织中积累。1)铁是氧化自由基介导的细胞和组织损伤的重要催化剂。受影响患者的脑脊液显示铁浓度增加三倍，这与超氧化物歧化酶活性和脂质过氧化产物增加有关。这些发现支持了铁介导的脂质过氧化有助于尖状纤溶酶血症患者神经退行性变的假设。这种测量可能对评估疾病进展以及铁螯合和其他治疗干预的结果有价值。2)筛选4990例健康成人血清铜蓝蛋白浓度。随后的突变等位基因序列测定显示3个突变（1个纯合子和5个杂合子）。基因频率为70x/ 100000。在日本，据估计，在非近亲婚姻的情况下，急性纤溶酶血症的发病率约为每200万人中有一人。3)我们报告一位患有帕金森病和晚发性糖尿病的70岁妇女，她的铜蓝蛋白基因发生了新的突变。铜蓝蛋白基因的核苷酸序列分析显示，在第11外显子有1个bp的缺失（G: nt 2068）。该突变产生帧移位，导致在a690处过早终止。

项目成果

Miyajima H et al: "CSF abnormalitics in patients with aceruloplasminemia"Neurology. 51・4. 1188-1190 (1998)

Miyajima H 等：“铜蓝蛋白血症患者的脑脊液异常”Neurology 51・4（1998）。

Kohno S et al.: "Aceraloplasminenia with a novel mutation is associated with parl*insou**m"

Kohno S 等人：“具有新突变的针蓝蛋白血症与 parl*insou**m 相关”

Miyajima H.: "Increased very long-chain fatty acids in erythrocyte membranes of patients with aceruloplasminemia" Neurology. 50・1. 130-136 (1998)

Miyajima H.：“铜蓝蛋白血症患者的红细胞膜中的极长链脂肪酸增加”，《神经病学》50・1（1998）。

kohno S ct al: "Acerulaplasminemia with a novel mutation is associated with parkinsonism"Neurogenct. (in press). (2000)

kohno S ct al：“具有新突变的血浆铜蓝蛋白血症与帕金森症有关”Neurogenct。

Miyajima H.: "CSF abnormalities in patients with aceruloplasminemia" Neurology. 51・4. 1188-1190 (1998)

Miyajima H.：“铜蓝蛋白血症患者的脑脊液异常”神经病学 51・4（1998）。