HUMAN BIOCHEMICAL GENETICS

人类生化遗传学

• 批准号: 4693717
• 负责人: W A GAHL
• 金额: --
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/4693717
• 关键词: Fabry's disease; I cell disease; aminoacid metabolism; aminoacid transport; betaine compound; bone density; carnitine; child (0-11); computed axial tomography; cysteamine; cystine; cystinosis; deToni Fanconi syndrome; heterozygote; homocystinuria; human subject; human therapy evaluation; human tissue; inborn biological transport disorder; inborn lysosomal enzyme disorder; inborn metabolism disorder; lysosomes; metabolism disorder chemotherapy; molecular genetics; nonelectrolyte transport; prolactin; sialate; sulfur compounds; thyrotropin releasing hormone; tissue /cell culture

(1) Cystine movement out of lysosomes is enhanced by permeant potassium ions. Cysteamine depletes cystinotic lysosomes of cystine by forming cysteine-cysteamine mixed disulfide, which leaves the lysosome by a process not requiring the cystine carrier, which is defective in cystinosis. (2) Children with nephropathic cystinosis manifest improved growth and slowed renal deterioration if treated with cysteamine before 3 years of age. Children with renal Fanconi syndrome exhibited a marked deficiency of plasma and muscle free carnitine due to failure of the kidney to reabsorb carnitine. Carnitine supplementation restored plasma free carnitine levels to normal. Cystinotic children receiving cysteamine chronically displayed a blunted prolactin response to TRH. Heterozygote testing verified that the occurrence of Fabry disease and cystinosis in 2 siblings represented a rare manifestation of the two classical mutations in a single family. Late complications of cystinosis were shown to include involvement of the CNS, eyes, pancrease, lungs, and salivary glands. (3) Mucolipidosis II, or I-cell, fibroblasts were shown to store cystine due to impaired egress of cystine out of isolated granular fractions. The half-times for such egress were over 100 min for I-cell lysosomes and 40 min for normals. (4) Free sialic acid storage disease fibroblasts store free sialic acid in their lysosomes. Sialic acid egress from these lysosomes was negligible compared with normals, suggesting that the disorder represents a defect in lysosomal transport of free sialic acid. (5) A normal 31-year-old man with methionine adenosyltransferase deficiency offers 25 years of additional natural history to the disorder, previously described only in 5 children age 6 or below. (6) Six patients with homocystinuria are receiving betaine therapy in a double-blind, placebo-controlled study to determine if the drug improves vertebral body bone density, measured by CT scan. (7) Cysteamine charge-shifted apolipoprotein E molecules in vitro and in vivo, making feasible the treatment by oral cysteamine of diseases with cysteine-for-arginine substitutions which result in nonfunctional proteins.

（1）通过渗透性钾增强了溶酶体的胱氨酸运动 离子。 氰碱通过形成囊肿的囊肿性溶酶体耗尽 半胱氨酸 - 天气联氨酸混合二硫化物，它通过 过程不需要胱氨酸载体，该载体有缺陷 囊肿。 （2）患有肾病性囊肿病的儿童已改善 如果在之前用cysteamine治疗的生长和肾脏恶化减慢 3岁。 肾芬科综合症的儿童表现出明显的 由于失败的血浆和无肌肉肉碱的缺乏 肾脏到吸收肉碱。 肉碱补充恢复了血浆 免费的肉碱水平正常。 囊肿儿童接收cysteamine 长期表现出对TRH的催乳素反应钝化。 杂合子 测试验证了Fabry病和膀胱变性的发生 2个兄弟姐妹代表了两个经典突变的罕见表现 在一个家庭中。 膀胱炎的晚期并发症已显示为 包括CNS的参与，眼睛，胰腺，肺和唾液 腺体。 （3）粘膜脂肪性病II或I细胞，成纤维细胞已显示可储存 胱氨酸由于胱氨酸出口受损而导致的颗粒 分数。 I-Cell的此类出口的半次超过100分钟 溶酶体和40分钟的正常体。 （4）游离唾液酸储存疾病 成纤维细胞将游离唾液酸储存在其溶酶体中。 唾液酸出口 从这些溶酶体中，与正： 该疾病代表游离唾液的溶酶体运输缺陷 酸。 （5）一个正常的31岁男性患有蛋氨酸腺苷转移酶 缺乏症为疾病提供25年的额外自然病史， 先前仅在6岁或以下的5名儿童中描述。 （6）六名患者 有同囊尿症正在接受双盲的Betaine疗法， 安慰剂对照研究以确定药物是否改善椎体 骨密度，通过CT扫描测量。 （7）cysteamine thick换移 载脂蛋白E分子在体外和体内，使可行 用半胱氨酸 - 精氨酸的口服cysteamine治疗 导致非功能蛋白的取代。