HUMAN BIOCHEMICAL GENETICS

1.该科成员进行了突变 肾性胱氨酸病108例分析 表明44%的人是典型的65 kb纯合子 缺失发生在北欧。他们还描述了18个新的 CTNS基因的突变，并建立了胱氨酸病的临床 严重程度评分对表型/基因相关很有用。这个 科室继续治疗100多名患者的口服和外用 (眼药水)半胱胺。2.UDP-GlcNAc的人类基因 克隆了2-表位异构酶，并对该基因(R266W， 在3例唾液酸尿症患者中发现R266E和R263L)。 由于这种障碍是由于有缺陷的反馈抑制 由cMP-唾液酸组成的表异构体，定位突变在 密码子263和266将该区域定义为酶的变构 地点。在每种情况下，一个完全正常的第二等位基因指向 唾液酸尿症的显性遗传。3.74名患者 Hermansky Pudlak综合征(HPS)现已在 美国国立卫生研究院临床中心。来自波多黎各西北部的患者，谁 都是HPS-1基因16个碱基重复的纯合子 患上肺纤维化的风险增加。因为我们有 描述了两个波多黎各人和十几个非波多黎各人 患有HPS的Rican患者缺乏HPS-1突变，有 疾病中存在相当大的基因座异质性。事实上，成员们 该科已确定两名HPS患者为复合体 适配器AP-3的b3A亚单位突变的杂合子 与囊泡运输和货物有关的蛋白质复合体 分类。这些患者是HPS模型小鼠的对应者 被称为珍珠，代表了人类第一个突变的成分 一种涉及囊泡运输的蛋白质涂层。

1. Members of the Section have performed mutation analysis on 108 patients with nephropathic cystinosis, demonstrating that 44% are homozygous for a typical, 65-kb deletion arising in northern Europe. They also described 18 new mutations in the CTNS gene, and established a cystinosis clinical severity score useful for phenotype/genotype correlations. The Section continues to treat over 100 patients with oral and topical (eyedrop) cysteamine. 2. The human gene for UDP-GlcNAc 2-epimerase was cloned, and mutations in this gene (R266W, R266E, and R263L) were identified in three patients with sialuria. Since this disorder is due to defective feedback inhibition of the epimerase by CMP-sialic acid, the location of the point mutations in codons 263 and 266 defines this region as the enzyme's allosteric site. A completely normal second allele in each case points to dominant inheritance for sialuria. 3. Seventy-four patients with Hermansky Pudlak syndrome (HPS) have now been examined at the NIH Clinical Center. Patients from northwest Puerto Rico, who are all homozygous for a 16-bp duplication in the gene HPS-1, are at increased risk for developing pulmonary fibrosis. Since we have described two Puerto Rican and more than a dozen non-Puerto Rican patients with HPS who lack a mutation in HPS-1, there is considerable locus heterogeneity in the disease. In fact, members of the Section have identified two HPS patients who are compound heterozygotes for mutations in the b3A subunit of AP-3, an adaptor protein complex responsible for vesicular trafficking and cargo sorting. These patients, the counterparts of an HPS model mouse called pearl, represent the first human mutations in a component of a protein coat involving vesicular trafficking.