Members of the Section have linked the cystinosis gene to marker D17S1584 on the short arm of chromosome 17 with a maximum lod score of 10.89 at theta = 0.03. They have constructed a YAC contig spanning the region of interest in an attempt to isolate the cystinosis gene itself. Several mutations in the Menkes disease gene have been identified in patients with this X-linked disorder, and genotypes have been correlated with responsiveness to early copper histidine therapy in two families. In one, a G to T transversion at a -1 exonic splice donor site caused a glutamine to histidine substitution at codon 724, with skipping of one, two, or three exons, and premature termination. Two related children with this mutation were treated early in life with copper histidine, and neither had a normal neurodevelopmental outcome, suggesting that the Q724H mutation did not preserve sufficient residual Menkes ATPase activity for significant clinical benefit to accrue from copper replacement. In contrast, a different family exhibited a 5-base duplication at a splice acceptor site just upstream of a 226 bp exon in the middle of the Menkes coding sequence, with one transcript which contained a deletion of the preceeding 77 bp exon. This created an open reading frame, and RNAse protection studies revealed 25% of the normal Menkes gene transcript. One affected boy in this family, treated with copper from 8 days of age, now has normal neurodevelopment at 14 months of age. Analysis of N-linked oligosaccharides on serum glycoproteins from patients with Carbohydrate Deficient Glycoprotein Syndrome revealed heterogeneity in the biochemical basis of the disease, with some patients demonstrating a defect early in the formation of dolichol- oligosaccharides. A tyrosine transport system has been characterized in the melanosomes of murine melanocytes and found to be functional in the pink-eyed dilution mutant, the murine homologue of oculocutaneous albinism type II. Dolichols have been identified as components of the ceroid lipofuscin which is stored in the cellular lysosomes of patients with Hermansky-Pudlak syndrome, a type of albinism with a platelet storage pool defect.
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