The first two steps in the mammalian
lysine-degradation pathway are catalyzed by
lysine-ketoglutarate reductase and
saccharopine dehydrogenase, respectively, resulting in the conversion of
lysine to
alpha-aminoadipic semialdehyde. Defects in one or both of these activities result in
familial hyperlysinemia, an autosomal recessive condition characterized by
hyperlysinemia, lysinuria, and variable
saccharopinuria. In yeast,
lysine-ketoglutarate reductase and
saccharopine dehydrogenase are encoded by the LYS1 and LYS9 genes, respectively, and we searched the available sequence databases for their human homologues. We identified a single
cDNA that encoded an apparently bifunctional
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 bifunctional
protein has previously been referred to as "
alpha-aminoadipic semialdehyde synthase," and we have tentatively designated this gene "AASS." The AASS
cDNA contains an open reading frame of 2,781 bp 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
DNA from a single patient with
hyperlysinemia (JJa). The patient is the product of a consanguineous mating and is homozygous for an out-of-frame 9-bp deletion 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 AASS 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 of
hyperlysinemia.