Identification of the alpha-aminoadipic semialdehyde synthase gene, which is defective in familial hyperlysinemia

The first two steps in the mammalian lysine-degradation pathway are catalyz ed by lysine-ketoglutarate reductase and saccharopine dehydrogenase, respec tively, resulting in the conversion of lysine to alpha-aminoadipic semialde hyde. Defects in one or both of these activities result in familial hyperly sinemia, an autosomal recessive condition characterized by hyperlysinemia, lysinuria, and variable saccharopinuria. In yeast, lysine-ketoglutarate red uctase and saccharopine dehydrogenase are encoded by the LYS1 and LYS9 gene s, respectively, and we searched the available sequence databases for their human homologues. We identified a single cDNA that encoded an apparently b ifunctional protein, with the N-terminal half similar to that of yeast LYS1 and with the C-terminal half similar to that of yeast LYS9. This bifunctio nal protein has previously been referred to as "alpha-aminoadipic semialdeh yde synthase," and we have tentatively designated this gene "AASS." The AAS S cDNA contains an open reading frame of 2,781 be predicted to encode a 927 -amino-acid-long protein. The gene has been sequenced and contains 24 exons scattered over 68 kb and maps to chromosome 7q31.3. Northern blot analysis revealed the presence of several transcripts in all tissues examined, with the highest expression occurring in the liver. We sequenced the genomic DN A from a single patient with hyperlysinemia (JJa). The patient is the produ ct of a consanguineous mating and is homozygous for an out-of-frame 9-bp de letion in exon 15, which results in a premature stop codon at position 534 of the protein. On the basis of these and other results, we propose that AA SS catalyzes the first two steps of the major lysine-degradation pathway in human cells and that inactivating mutations in the AASS gene are a cause o f hyperlysinemia.