HUMAN BIOCHEMICAL GENETICS

1.序列分析显示，中间或眼胱氨酸病患者有一个严重的（经典）和一个CTNS基因的轻度突变，验证这些变异是等位基因肾病胱氨酸病。在临床工作中，定期随访100例患者，以确定早期口服半胱胺治疗是否可预防疾病的晚期并发症。一个新的并发症，肺功能障碍，是首次报告的成人患者，其次是该组。在1976年至2000年期间对177名患者进行的一项研究中报告了角膜晶体积聚的自然史及其半胱胺滴眼液治疗。2.该科的成员确定了世界上五个已报告的sidelia病例之一的分子缺陷，即G到A的变化导致R266 Q取代。3.该小组继续对100多名Hermansky-Pudlak综合征（HPS）患者的临床，生化，分子和细胞生物学基础进行表征。在与其他NIH研究者的合作中，该疾病的皮肤病学、眼科和肺部表现在不同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，该科正在积极寻找参与囊泡形成和运输的候选基因，作为遗传学上未确定的患者中这种疾病的原因。与CBMB的Bonifacino博士合作，HPS 1基因的蛋白质产物被表征为主要是细胞质，具有少量的膜组分。来自HPS-2患者的B淋巴母细胞，缺乏负责新囊泡形成的衔接蛋白复合物-3，被发现以正常方式运输主要组织相容性复合物II类分子。该科成员还报告了HPS 1基因中的一种新的多态性和一种与HPS 1同源的部分假基因。 4.黑酸尿症是一种以尿黑酸积累和骨关节破坏为特征的疾病，研究方案已经启动。其目的是开发严重程度评分，作为即将到来的治疗方案的结果参数，并开发与其他医生和患者分享的专业知识。

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. B-lymphoblasts from an HPS-2 patient, with deficiency of the adaptor protein complex-3 responsible for new vesicle formation, were found to traffic major histocompatibility complex class II molecules in a normal fashion. Members of the Section also reported a new polymorphism in the HPS1 gene and a partial pseudogene homologous to HPS1. 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.