HUMAN BIOCHEMICAL GENETICS

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1. Members of the Section continue to perform linkage analysis on several families with nephropathic cystinosis. To date, 75% of the human genome has been excluded as the location of the cystinosis gene. 2. Several mutations in the Menkes disease gene have been identified in patients with this X-linked disorder. Four members of a family with mild Menkes disease displayed an A to T transversion in the +3 splice donor site of an intron near the 3' end of the Menkes gene, resulting in deletion of a 118 bp exon, with substantial correct splicing. One patient with occipital horn syndrome had an A to G transition in the -2 exonic splice donor site in the middle of the Menkes gene resulting in deletion of a 92 bp exon, again with residual normal splicing. Two related patients with classical Menkes disease exhibited a G to T transversion at a -1 exonic splice donor site causing a glutamine to histidine substitution at codon 724, skipping of one, two, or three exons, and premature termination. 3. Analysis of N-linked oligosaccharides on serum glycoproteins from patients with Carbohydrate Deficient Glycoprotein Syndrome indicates a defect early in the formation of dolichol-oligosaccharides. 4. Mutational analysis of the fumarylacetoacetase gene in a 12-year old boy with chronic tyrosinemia type I revealed two defects, a missense mutation causing a tryptophan to glycine alteration in codon 234, and a splicing mutation in the +5 position of intron 12 causing exon skipping.