Succinic semialdehyde dehydrogenase (SSADH) deficiency, a rare metabolic disorder of 4-aminobutyric acid degradation, has been identified in similar to 150 patients. Affected individuals accumulate large quantities of 4-hydroxybutyric acid, a compound with a wide range of neuropharmacological activities, in physiological fluids. As a first step in beginning an investigation of the molecular genetics of SSADH deficiency, we have utilized SSADH cDNA and genomic sequences to identify two point mutations in the SSADH genes derived from four patients. These mutations, identified by standard methods of reverse transcription, PCR, dideoxy-chain termination, and cycle sequencing, alter highly conserved sequences at intron/exon boundaries and prevent the RNA-splicing apparatus from properly recognizing the normal splice junction. Each family segregated a mutation in a different splice site, resulting in exon skipping and, in one case, a frameshift and premature termination and, in the other case, an in-frame deletion in the resulting protein. Family members, including parents and siblings of these patients, were shown to be heterozygotes for the splicing abnormality, providing additional evidence for autosomal recessive inheritance. Our results provide the first evidence that 4-hydroxybutyric aciduria, resulting from SSADH deficiency, is the result of genetic defects in the human SSADH gene.

Chambliss, K., Hinson, D., Trettel, F., Malaspina, P., Novelletto, A., Jakobs, C., et al. (1998). Two exon-skipping mutations as the molecular basis of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria). AMERICAN JOURNAL OF HUMAN GENETICS, 63(2), 399-408 [10.1086/301964].

Two exon-skipping mutations as the molecular basis of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria)

MALASPINA, PATRIZIA;NOVELLETTO, ANDREA;
1998-01-01

Abstract

Succinic semialdehyde dehydrogenase (SSADH) deficiency, a rare metabolic disorder of 4-aminobutyric acid degradation, has been identified in similar to 150 patients. Affected individuals accumulate large quantities of 4-hydroxybutyric acid, a compound with a wide range of neuropharmacological activities, in physiological fluids. As a first step in beginning an investigation of the molecular genetics of SSADH deficiency, we have utilized SSADH cDNA and genomic sequences to identify two point mutations in the SSADH genes derived from four patients. These mutations, identified by standard methods of reverse transcription, PCR, dideoxy-chain termination, and cycle sequencing, alter highly conserved sequences at intron/exon boundaries and prevent the RNA-splicing apparatus from properly recognizing the normal splice junction. Each family segregated a mutation in a different splice site, resulting in exon skipping and, in one case, a frameshift and premature termination and, in the other case, an in-frame deletion in the resulting protein. Family members, including parents and siblings of these patients, were shown to be heterozygotes for the splicing abnormality, providing additional evidence for autosomal recessive inheritance. Our results provide the first evidence that 4-hydroxybutyric aciduria, resulting from SSADH deficiency, is the result of genetic defects in the human SSADH gene.
1998
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore BIO/18 - GENETICA
English
Con Impact Factor ISI
4 aminobutyric acid; 4 hydroxybutyric acid; succinate semialdehyde dehydrogenase; 4 aminobutyric acid metabolism; aciduria; article; autosomal recessive inheritance; controlled study; enzyme deficiency; exon; female; gene deletion; gene sequence; human; human cell; major clinical study; male; nucleotide sequence; point mutation; priority journal; RNA splicing; transcription termination; Aldehyde Oxidoreductases; Amino Acid Sequence; Base Sequence; Cells, Cultured; Consanguinity; Exons; Female; Heterozygote Detection; Humans; Hydroxybutyrates; Introns; Lymphocytes; Male; Metabolism, Inborn Errors; Molecular Sequence Data; Nuclear Family; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; Sequence Deletion; Succinate-Semialdehyde Dehydrogenase
Chambliss, K., Hinson, D., Trettel, F., Malaspina, P., Novelletto, A., Jakobs, C., et al. (1998). Two exon-skipping mutations as the molecular basis of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria). AMERICAN JOURNAL OF HUMAN GENETICS, 63(2), 399-408 [10.1086/301964].
Chambliss, K; Hinson, D; Trettel, F; Malaspina, P; Novelletto, A; Jakobs, C; Gibson, K
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/44419
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