Human Biochemical Genetics

1.序列分析显示，中度或眼部膀胱病患者的CTNS基因有一个严重(经典)和一个轻微的突变，证实这些变异与肾病性胱氨酸病是等位基因。在临床工作中，对100名患者进行定期跟踪，以确定早期口服半胱胺治疗是否可以防止疾病的晚期并发症。一种新的并发症，肺功能障碍，首次在成人患者中报告，随后该组患者。在1976年至2000年间对177名患者进行的一项研究中，报道了角膜晶体堆积的自然病史，以及半胱胺滴眼液的治疗。2.在世界上报告的五例唾液酸尿症中的一例中，该科成员确定了分子缺陷，即由G变为A，导致R266Q替换。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研究。在与其他NIH研究人员的合作下，这种疾病的皮肤病、眼科和肺部表现分别在不同的出版物中进行了描述，并与致病基因突变相关。HPS显示出明显的位点异质性，该部门正在热衷于寻找与囊泡形成和运输有关的候选基因，作为遗传不确定患者这种疾病的原因。在与CBMB的Bonifacino博士的合作下，HPS1基因的蛋白质产物被鉴定为主要是细胞质的，含有少量的膜成分。该组成员还报告了HPS1基因的一个新的多态和一个与HPS1部分同源的假基因。一种新的导致HPS的基因HPS3被鉴定出来，以及几个突变。4.已经启动了一项研究尿酸尿症的议定书，这是一种以同种酸积聚和骨骼和关节破坏为特征的疾病。其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。

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.