Human Biochemical Genetics

人类生化遗传学

• 批准号: 7316042
• 负责人: William Allen Gahl
• 金额: --
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 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/7316042
• 关键词: Human; Biochemical; Genetics

Summary: The Section on Human Biochemical Genetics studies selected inborn errors of metabolism to provide insight into cellular mechanisms and care for neglected groups of rare disease patients. 1. Members of the Section admitted approximately 60 individuals with cystinosis as inpatients or outpatients to the NIH Clinical Research Center, documenting the beneficial effects of oral cysteamine therapy with respect to growth, renal function, and ophthalmic abnormalities. They also reported liver involvement with portal hypertension and coronary artery disease with vascular calcifications as late complications of cystinosis in patients not receiving oral cysteamine therapy. In collaboration with colleagues in the National Eye Institute, the Section described the ophthalmic histopathology of cystinosis, and continues to provide cysteamine eyedrops to patients suffering from photophobia due to corneal cystine crystal accumulation. The collaborative group continues to work to bring cysteamine eyedrops to New Drug Approval by the FDA. The Section serves as the world authority on cystinosis, responding to scores of inquires every year from patients and physicians throughout the world. 2. The Section continues its investigations into alkaptonuria, a disorder of accumulation of homogentisic acid due to deficiency of homogentisate 1,2-dioxygenase. In collaboration with the Clinical Center's Rehabilitation Medicine Department, members of the Section have comprehensively described the musculoskeletal manifestations and progression to disability of alkaptonuria patients. The Section has also successfully enrolled 40 alkaptonuria subjects in a randomized clinical trial of nitisinone, a powerful inhibitor of the enzyme that produces homogentisic acid, using hip range of motion as the primary outcome parameter. An Investigational New Drug (IND) exemption has been obtained from the FDA for this study. 3. The Section remains the only center in the world investigating both the clinical and basic aspects of Hermansky-Pudlak syndrome (HPS), a rare disorder of oculocutaneous albinism and bleeding due to abnormal formation of intracellular vesicles such as melanosomes and platelet dense bodies. There are 8 genetic subtypes of this disease, and the Section has cared for more than 160 affected individuals. In basic studies, members of the Section and their collaborators reported a normal contingent of alpha granules in HPS platelets, which are known to lack dense granules. They demonstrated that the HPS3 protein interacts with clathrin; this finding helps explain the function of HPS3 in intracellular trafficking. In clinical studies, the group and collaborators described the first successful lung transplantation in an HPS patient, the ocular pathology of HPS, and the granulomatous colitis of HPS in relation to the particular subtypes. Physicians in the Section have also initiated a randomized, placebo-controlled clinical trial of the antifibrotic agent, pirfenidone, to combat the fatal pulmonary fibrosis of HPS. The outcome parameter is change in forced vital capacity. An IND has been obtained, and enrollment has begun. In parallel with this clinical trial, Section physicians are investigating the etiology of the lung fibrosis through studies of cytokines in HPS pulmonary lavage fluid. 4. The Section is performing linkage studies of Gray Platelet Syndrome, a disorder in which platelet alpha granules are absent and patients suffer from a bleeding diathesis. 5. The Section has also initiated studies to identify the gene responsible for White Platelet Syndrome, a macrothrombocytopenia associated with multiple Golgi regions in platelets. 6. An ongoing clinical protocol investigates Autosomal Recessive Polycystic Kidney Disease and Congenital Hepatic Fibrosis to define the natural history and determine outcome parameters for future therapeutic intervention. Approximately 40 patients have been evaluated in this study, and the Section, along with the Office of Rare Diseases, sponsored and published a summary of the proceedings of a workshop on ARPKD/CHF attended by national authorities in the field. Detailed descriptions of the radiographic features of ARPKD/CHF are being prepared for publication. 7. A clinical protocol investigating the natural history of Hutchinson-Gilford Progeria Syndrome has been approved, and 15 patients with this premature aging syndrome have been enrolled. The findings are being compiled. 8. Several patients were seen with Chediak-Higashi disease, a disorder of large intracellular granules and a tendency toward fatal infections. The Section described a severely affected infant and a mildly affected adult, identifying the causative mutations in the CHS1 gene and providing genotype-phenotype correlations on clinical, molecular, and cell biological levels. 9. In collaboration with the Cell Biology of Metabolic Disorders Unit, members of the Section have pursued a rare muscle disease, Hereditary Inclusion Body Myopathy (HIBM). The causative gene is GNE, which encodes the bifunctional enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, responsible for catalyzing the first two steps in sialic acid synthesis. Sialic acid serves as the terminal sugar on glycoproteins that decorate plasma membranes and modulate cell-cell interactions; muscle proteins such as alpha-dystroglycan are heavily sialylated, and the myopathy of HIBM has been attributed to hyposialylation of alpha-dystroglycan and other muscle proteins. In addition to collaborating on HIBM basic research projects and animal model studies with the Unit, the Section has performed a pilot study of intravenous immune globulin G for treating HIBM, based upon the high sialic acid content of immune globulin. In four treated patients, muscle strength and functional activity improved considerably, prompting further investigations into providing sialic acid or a precursor to HIBM patients.

概括： 人类生化遗传学研究部分选择了先天性代谢缺陷，以深入了解细胞机制并为被忽视的罕见病患者群体提供护理。 1. 该部门的成员将大约 60 名胱氨酸中毒患者收治到 NIH 临床研究中心住院或门诊，记录了口服半胱胺治疗对生长、肾功能和眼部异常的有益效果。他们还报告称，在未接受口服半胱胺治疗的患者中，肝脏受累伴有门脉高压和伴有血管钙化的冠状动脉疾病，这是胱氨酸中毒的晚期并发症。该科与国家眼科研究所的同事合作，描述了胱氨酸中毒的眼科组织病理学，并继续为因角膜胱氨酸晶体积累而患有畏光的患者提供半胱胺滴眼剂。该合作小组将继续努力使半胱胺滴眼剂获得 FDA 的新药批准。该科是胱氨酸病的世界权威，每年都会答复来自世界各地患者和医生的大量询问。 2. 该科继续研究尿黑酸尿症，这是一种由于尿黑酸 1,2-双加氧酶缺乏而导致尿黑酸蓄积的疾病。该科成员与临床中心康复医学科合作，全面描述了黑酸尿症患者的肌肉骨骼表现和残疾进展。该科还成功招募了 40 名黑酸尿症受试者参加一项尼替西农随机临床试验，尼替西农是一种产生尿黑酸的酶的强效抑制剂，使用髋关节活动范围作为主要结果参数。本研究已获得 FDA 的研究性新药 (IND) 豁免。 3. 该科仍然是世界上唯一研究赫曼斯基-普德拉克综合征 (HPS) 临床和基础方面的中心，这是一种罕见的眼皮肤白化病和由于细胞内囊泡（如黑素体和血小板致密体）形成异常而导致出血的疾病。这种疾病有 8 种遗传亚型，该科已照顾了 160 多名受影响的个体。在基础研究中，该部门的成员及其合作者报告了 HPS 血小板中存在正常的 α 颗粒，而众所周知，HPS 血小板缺乏致密颗粒。他们证明 HPS3 蛋白与网格蛋白相互作用；这一发现有助于解释 HPS3 在细胞内运输中的功能。在临床研究中，该小组和合作者描述了首次成功的 HPS 患者肺移植、HPS 的眼部病理学以及与特定亚型相关的 HPS 肉芽肿性结肠炎。该科的医生还启动了一项抗纤维化药物吡非尼酮的随机、安慰剂对照临床试验，以对抗 HPS 的致命性肺纤维化。结果参数是用力肺活量的变化。 IND 已获得，注册已开始。与这项临床试验同时进行的，科室医生正在通过研究 HPS 肺灌洗液中的细胞因子来研究肺纤维化的病因。 4. 该科正在开展灰血小板综合征的关联研究，灰血小板综合征是一种血小板α颗粒缺失且患者患有出血素质的疾病。 5. 该科还启动了研究，以确定导致白血小板综合征的基因，白血小板综合征是一种与血小板中多个高尔基体区域相关的巨血小板减少症。 6. 一项正在进行的临床方案研究常染色体隐性多囊肾病和先天性肝纤维化，以确定自然史并确定未来治疗干预的结果参数。这项研究对大约 40 名患者进行了评估，该科与罕见病办公室共同主办并出版了由该领域国家当局参加的 ARPKD/CHF 研讨会的会议记录摘要。 ARPKD/CHF 放射学特征的详细描述正在准备出版。 7. 一项调查哈钦森-吉尔福德早衰综合症自然史的临床方案已获得批准，并已入组 15 名患有这种早衰综合症的患者。调查结果正在整理中。 8. 几名患者被发现患有 Chediak-Higashi 病，这是一种大细胞内颗粒疾病，有致命感染的倾向。该部分描述了一名严重受影响的婴儿和一名轻度受影响的成人，确定了 CHS1 基因的致病突变，并提供了临床、分子和细胞生物学水平上的基因型-表型相关性。 9. 该科成员与代谢紊乱细胞生物学组合作，研究了一种罕见的肌肉疾病，即遗传性包涵体肌病 (HIBM)。致病基因是 GNE，它编码双功能酶 UDP-N-乙酰氨基葡萄糖 2-差向异构酶/N-乙酰甘露糖胺激酶，负责催化唾液酸合成的前两个步骤。唾液酸作为糖蛋白的末端糖，装饰质膜并调节细胞间相互作用； α-肌营养不良聚糖等肌肉蛋白被严重唾液酸化，HIBM 肌病归因于 α-肌营养不良聚糖和其他肌肉蛋白的低唾液酸化。除了与该科合作开展HIBM基础研究项目和动物模型研究外，该科还根据免疫球蛋白高唾液酸含量进行了静脉注射免疫球蛋白G治疗HIBM的初步研究。在四名接受治疗的患者中，肌肉力量和功能活动显着改善，促使进一步研究向 HIBM 患者提供唾液酸或前体。