HUMAN BIOCHEMICAL GENETICS

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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. B-lymphoblasts from an HPS-2 patient, with deficiency of the adaptor protein complex-3 responsible for new vesicle formation, were found to traffic major histocompatibility complex class II molecules in a normal fashion. Members of the Section also reported a new polymorphism in the HPS1 gene and a partial pseudogene homologous to HPS1. 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.