HUMAN BIOCHEMICAL GENETICS

点击翻译按钮获取中文摘要

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.