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Identification of the alpha-aminoadipic semialdehyde synthase gene, which is defective in familial hyperlysinemia.
- Source :
-
American journal of human genetics [Am J Hum Genet] 2000 Jun; Vol. 66 (6), pp. 1736-43. Date of Electronic Publication: 2000 Apr 20. - Publication Year :
- 2000
-
Abstract
- 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.
- Subjects :
- Amino Acid Sequence
Base Sequence
Chromosomes, Human, Pair 7 genetics
Cloning, Molecular
Consanguinity
DNA Mutational Analysis
Exons genetics
Female
Gene Expression Profiling
Genes, Recessive genetics
Homozygote
Humans
In Situ Hybridization, Fluorescence
Lysine metabolism
Male
Molecular Sequence Data
Multienzyme Complexes chemistry
Multienzyme Complexes metabolism
Physical Chromosome Mapping
RNA Splice Sites genetics
RNA, Messenger analysis
RNA, Messenger genetics
Saccharopine Dehydrogenases chemistry
Saccharopine Dehydrogenases metabolism
Sequence Alignment
Sequence Deletion genetics
Hyperlysinemias enzymology
Hyperlysinemias genetics
Multienzyme Complexes genetics
Mutation genetics
Saccharopine Dehydrogenases genetics
Subjects
Details
- Language :
- English
- ISSN :
- 0002-9297
- Volume :
- 66
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- American journal of human genetics
- Publication Type :
- Academic Journal
- Accession number :
- 10775527
- Full Text :
- https://doi.org/10.1086/302919