HUMAN BIOCHEMICAL GENETICS

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Members of the Section have determined the CTNS mutations responsible for benign (ocular) and intermediate cystinosis, and have reviewed the worlds reported CTNS mutations. They have developed a multiplex PCR amplification method for diagnosing the presence of the 57-kb deletion present in 56% of 216 cytinosis alleles tested. The Section continues to treat over 100 patients with oral and topical (eyedrop) cysteamine. 2. In collaboration with NHGRI investigators, a new gene adjacent to CTNS was discovered. The gene, called CARKL, presumably produces a carbohydrate kinase and may distinguish cystinosis patients bearing the 57-kb deletion from nondeletion patients. It has a 1434 bp open reading frame with 7 exons encoding a 478 amino acid protein. Expression of a 3.9 kb transcript occurs prominently in liver, kidney, and pancreas. 3. The fifth patient in the world with sialuria has been characterized. This 7-year old Portuguese girl carries a single copy of a UDP-GlcNAc 2-epimerase gene containing an R266Q mutation, and the resulting enzyme is inhibited only 26% by 100 micromolar CMP-sialic acid (normal, 79%). 4. More than 95 patients with Hermansky Pudlak syndrome (HPS) have now been examined at the NIH Clinical Center, and the pulmonary, dermatologic, and ophthalmologic aspects of the disorder have been described. Members of the Section have also identified and clinically characterized two HPS patients who are compound heterozygotes for mutations in the beta-3A subunit of AP-3, an adaptor protein complex responsible for vesicular trafficking and cargo sorting. - Cystinosis, sialuria, Hermansky-Pudlak syndrome, vesicular trafficking, mutation analysis - Human Subjects