Human Biochemical Genetics

1. 序列分析显示，中度或眼胱氨酸病患者在CTNS基因中有一个严重（经典）和一个轻度突变，证实这些变异与肾病胱氨酸病是等位基因。在临床工作中，对100名患者进行定期随访，以确定早期口服半胱胺治疗是否能预防疾病的晚期并发症。一种新的并发症，肺功能障碍，首次报道在成人患者随访组。在1976年至2000年期间对177名患者进行的一项研究中，报告了角膜晶体积累的自然历史及其用半胱胺滴眼液的治疗。2. 该部门的成员确定了分子缺陷，一个G到a的变化导致R266Q取代，在世界上报道的五个唾液尿病例之一。3. 该小组继续在临床、生化、分子和细胞生物学基础上对100多名Hermansky-Pudlak综合征（HPS）患者进行表征。在与其他NIH研究者的合作下，该疾病的皮肤、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表现出明显的基因座异质性，该部门正在积极寻找参与囊泡形成和运输的候选基因，以确定遗传不明患者的这种疾病的病因。在与CBMB的Bonifacino博士的合作中，HPS1基因的蛋白产物主要是细胞质的，有少量的膜成分。该组成员还报告了HPS1基因的新多态性和部分同源于HPS1的假基因。一个新的基因，HPS3，导致HPS被确定，以及几个突变。4. 一种以均质酸积累和骨骼和关节破坏为特征的疾病——尿酸症的研究方案已经启动。目的是开发严重性评分，作为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。

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.