Human Biochemical Genetics

人类生化遗传学

• 批准号: 6829337
• 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/6829337
• 关键词: albinism; cell components; cytogenetics; enzyme deficiency; gene expression; gene mutation; genetic disorder; human genetic material tag; human subject; inborn aminoacid metabolism disorder; molecular genetics; orphan disease /drug; phenylacetates; platelet disorder; polycystic kidney; tissue /cell culture

The Section on Human Biochemical Genetics studies selected inborn errors of metabolism to provide insight into cellular mechanisms and care for abandoned populations of patients. 1. Hermansky-Pudlak syndrome (HPS) is a rare disorder of oculocutaneous albinism and bleeding due to abnormal formation of melanosomes and platelet dense bodies. There are 7 genetic subtypes of this disease. Members of the Section described 6 new, non-Puerto Rican HPS-1 patients along with 4 novel HPS1 mutations, and 7 new, non-Puerto Rican HPS-4 patients having 3 novel HPS4 mutations. We continue to define the natural history of clinical involvement in the subtypes of HPS, and to perform cell biological studies of the movement of intracellular vesicles in these disorders. 2. This year members of the Section admitted more than 70 cystinosis patients to the Clinical Center, following their treatment with cysteamine and documenting the presence or absence of nonrenal complications of the disorder. One 25-year old man had coronary artery disease, and this is now being reported as a late complication of cystinosis. One woman carrying the diagnosis of ocular cystinosis was diagnosed instead with multiple myeloma. Two siblings treated well with cysteamine were reported to have excellent kidney function and growth at ages 14 and 8. In collaboration with the National Eye Institute, members of the Section continue to investigate cysteamine eyedrops for the treatment of corneal cystine crystals. 3. The Section has expanded its expertise in alkaptonuria, a disorder of accumulation of homogentisic acid due to deficiency of homogentisate 1,2-dioxygenase. The Section documented the natural history of the disease with respect to joints, kidney stones, and cardiac valves, and began therapy in 5 patients with nitisinone, which reduced the toxic homogentisic acid by 95%. Mutation analysis was also performed in patients enrolled in the Section?s studies. 4. Members of the Section diagnosed and described three different patients with disorders of free sialic acid metabolism, i.e., Salla disease and Infantile Free Sialic Acid Storage Disease. These disorders results from defective sialin, the lysosomal membrane transport protein which carries free sialic acid out of lysosomes. 5. The Section also studied selected rare disease patients, including two with Gray Platelet Syndrome and three with Hereditary Inclusion Body Myopathy. The deficient enzyme in this latter disease, UDP-GlcNAc 2-epimerase, was assayed in cultured fibroblasts. Mutation analysis was also performed on the patients? DNA. Protocols were initiated to find the gene causing Gray Platelet Syndrome and to document the natural history of Autosomal Recessive Polycystic Kidney Disease and Congenital Hepatic Fibrosis.

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和对被遗弃的患者群体的护理。 1. 赫曼斯基-普德拉克综合征（HPS）是一种罕见的眼皮肤白化病和因黑素体和血小板致密体形成异常而出血的疾病。这种疾病有7种遗传亚型。该部门的成员描述了 6 名新的非波多黎各 HPS-1 患者以及 4 种新的 HPS1 突变，以及 7 名新的非波多黎各 HPS-4 患者，具有 3 种新的 HPS4 突变。我们继续定义 HPS 亚型临床参与的自然史，并对这些疾病中细胞内囊泡的运动进行细胞生物学研究。 2. 今年，该科成员将 70 多名胱氨酸中毒患者收治至临床中心，接受半胱胺治疗并记录该疾病是否存在非肾脏并发症。一名 25 岁男性患有冠状动脉疾病，目前据报道这是胱氨酸中毒的晚期并发症。一名被诊断为眼部胱氨酸病的女性被诊断出患有多发性骨髓瘤。据报道，接受半胱胺治疗的两个兄弟姐妹在 14 岁和 8 岁时具有良好的肾功能和生长发育。该部门的成员与国家眼科研究所合作，继续研究半胱胺滴眼液治疗角膜胱氨酸晶体的效果。 3. 该科扩大了其在尿黑酸尿症方面的专业知识，尿黑酸尿症是一种由于尿黑酸 1,2-双加氧酶缺乏而导致尿黑酸蓄积的疾病。该科记录了该疾病在关节、肾结石和心脏瓣膜方面的自然史，并开始对 5 名患者进行尼替西农治疗，将有毒的尿黑酸减少了 95%。还对参加该部门研究的患者进行了突变分析。 4. 该科成员诊断并描述了三名不同的游离唾液酸代谢紊乱患者，即 Salla 病和婴儿游离唾液酸贮积病。这些疾病是由唾液酸蛋白缺陷引起的，唾液酸蛋白是一种溶酶体膜转运蛋白，可将游离唾液酸带出溶酶体。 5. 该科还对选定的罕见病患者进行了研究，其中包括两名灰血小板综合征患者和三名遗传性包涵体肌病患者。在培养的成纤维细胞中检测了后一种疾病中缺陷酶 UDP-GlcNAc 2-差向异构酶。还对患者进行了突变分析？脱氧核糖核酸。启动协议以寻找导致灰血小板综合征的基因，并记录常染色体隐性多囊肾病和先天性肝纤维化的自然史。