Human Biochemical Genetics

人类生化遗传学

• 批准号: 6549675
• 负责人: William Allen 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/6549675
• 关键词: albinism; blood coagulation disorders; cysteamine; cystinosis; dolichol; enzyme activity; gene expression; genotype; human genetic material tag; human subject; human therapy evaluation; inborn lysosomal enzyme disorder; inborn metabolism disorder; linkage mapping; longitudinal human study; melanins; metabolism disorder chemotherapy; molecular genetics; molecular pathology; neuronal ceroid lipofuscinosis; patient oriented research; pigmentation disorders; platelet disorder; ubiquinone

1. Sequence analyses revealed that patients with intermediate or ocular cystinosis have one severe (classical) and one mild mutation in the CTNS gene, verifying that these variants are allelic with nephropathic cystinosis. In clinical work, 100 patients are followed periodically to determine if early oral cysteamine therapy prevents late complications of the disease. One new complication, pulmonary dysfunction, was reported for the first time in adult patients followed by the group. The natural history of corneal crystal accumulation, and its treatment with cysteamine eyedrops, has been reported in a study of 177 patients followed between 1976 and 2000. 2. Members of the Section determined the molecular defect, a G to A change causing an R266Q substitution, in one of the five reported cases of sialuria in the world. 3. The group continues to characterize over 100 patients with Hermansky-Pudlak syndrome (HPS) on clinical, biochemical, molecular, and cell biological bases. In collaboration with other NIH investigators, the dermatologic, ophthalmologic, and pulmonary manifestations of the disease were described in separate publications and correlated with the causative genetic mutation. HPS displays clear locus heterogeneity, and the Section is avidly pursuing candidate genes involved in vesicle formation and trafficking as the cause of this disorder in genetically undefined patients. In collaboration with Dr. Bonifacino of the CBMB, the protein product of the HPS1 gene has been characterized as largely cytoplasmic, with a minor membrane component. Members of the Section also reported a new polymorphism in the HPS1 gene and a partial pseudogene homologous to HPS1. A new gene, HPS3, causing HPS was identified, along with several mutations. 4. A protocol to study alkaptonuria, a disorder characterized by accumulation of homogentisic acid and destruction of bones and joints, has been initiated. The intent is to develop severity scores to employ as outcome parameters for an upcoming treatment protocol, and to develop expertise to share with other physicians and patients.

1. 序列分析显示，中度或眼部胱氨酸沉积症患者的 CTNS 基因有 1 种严重（经典）突变和 1 种轻度突变，证实这些变异与肾病性胱氨酸沉积症是等位基因。在临床工作中，定期对 100 名患者进行随访，以确定早期口服半胱胺治疗是否可以预防该疾病的晚期并发症。一种新的并发症，即肺功能障碍，是首次在成年患者中报道，随后是该组报道。 1976 年至 2000 年间对 177 名患者进行的一项研究报告了角膜晶体积累的自然史及其用半胱胺滴眼剂的治疗。 2. 该部门的成员确定了分子缺陷，即导致 R266Q 取代的 G 到 A 的变化，这是世界上五例报告的唾液尿症病例之一。 3. 该小组继续从临床、生化、分子和细胞生物学基础上对 100 多名赫曼斯基-普德拉克综合征 (HPS) 患者进行表征。与其他 NIH 研究人员合作，该疾病的皮肤病学、眼科和肺部表现在单独的出版物中进行了描述，并与致病基因突变相关。 HPS 显示出明显的基因座异质性，该部门正在热切地寻找参与囊泡形成和运输的候选基因，作为遗传未定义患者中这种疾病的原因。与 CBMB 的 Bonifacino 博士合作，HPS1 基因的蛋白质产物被表征为主要是细胞质，具有少量的膜成分。该部门的成员还报告了HPS1基因的一个新的多态性以及与HPS1同源的部分假基因。鉴定出导致 HPS 的新基因 HPS3 以及一些突变。 4. 一项研究黑酸尿症的方案已经启动，黑酸尿症是一种以黑黑酸蓄积和骨骼和关节破坏为特征的疾病。目的是开发严重程度评分，用作即将到来的治疗方案的结果参数，并开发专业知识与其他医生和患者分享。