Skip to main content
PMC home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1998 Aug;63(2):399–408. doi: 10.1086/301964

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

K L Chambliss 1, D D Hinson 1, F Trettel 1, P Malaspina 1, A Novelletto 1, C Jakobs 1, K M Gibson 1
PMCID: PMC1377305  PMID: 9683595

Abstract

Succinic semialdehyde dehydrogenase (SSADH) deficiency, a rare metabolic disorder of 4-aminobutyric acid degradation, has been identified in approximately 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.

Full Text

The Full Text of this article is available as a PDF (2.8 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Cash C. D., Maitre M., Mandel P. Purification from human brain and some properties of two NADPH-linked aldehyde reductases which reduce succinic semialdehyde to 4-hydroxybutyrate. J Neurochem. 1979 Dec;33(6):1169–1175. doi: 10.1111/j.1471-4159.1979.tb05261.x. [DOI] [PubMed] [Google Scholar]
  2. Chambliss K. L., Caudle D. L., Hinson D. D., Moomaw C. R., Slaughter C. A., Jakobs C., Gibson K. M. Molecular cloning of the mature NAD(+)-dependent succinic semialdehyde dehydrogenase from rat and human. cDNA isolation, evolutionary homology, and tissue expression. J Biol Chem. 1995 Jan 6;270(1):461–467. doi: 10.1074/jbc.270.1.461. [DOI] [PubMed] [Google Scholar]
  3. Chambliss K. L., Gibson K. M. Succinic semialdehyde dehydrogenase from mammalian brain: subunit analysis using polyclonal antiserum. Int J Biochem. 1992 Sep;24(9):1493–1499. doi: 10.1016/0020-711x(92)90077-e. [DOI] [PubMed] [Google Scholar]
  4. Chambliss K. L., Lee C. F., Ogier H., Rabier D., Jakobs C., Gibson K. M. Enzymatic and immunological demonstration of normal and defective succinic semialdehyde dehydrogenase activity in fetal brain, liver and kidney. J Inherit Metab Dis. 1993;16(3):523–526. doi: 10.1007/BF00711671. [DOI] [PubMed] [Google Scholar]
  5. Gavel Y., von Heijne G. Cleavage-site motifs in mitochondrial targeting peptides. Protein Eng. 1990 Oct;4(1):33–37. doi: 10.1093/protein/4.1.33. [DOI] [PubMed] [Google Scholar]
  6. Gibson K. M., Baumann C., Ogier H., Rossier E., Vollmer B., Jakobs C. Pre- and postnatal diagnosis of succinic semialdehyde dehydrogenase deficiency using enzyme and metabolite assays. J Inherit Metab Dis. 1994;17(6):732–737. doi: 10.1007/BF00712016. [DOI] [PubMed] [Google Scholar]
  7. Gibson K. M., Christensen E., Jakobs C., Fowler B., Clarke M. A., Hammersen G., Raab K., Kobori J., Moosa A., Vollmer B. The clinical phenotype of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria): case reports of 23 new patients. Pediatrics. 1997 Apr;99(4):567–574. doi: 10.1542/peds.99.4.567. [DOI] [PubMed] [Google Scholar]
  8. Gibson K. M., Goodman S. I., Frerman F. E., Glasgow A. M. Succinic semialdehyde dehydrogenase deficiency associated with combined 4-hydroxybutyric and dicarboxylic acidurias: potential for clinical misdiagnosis based on urinary organic acid profiling. J Pediatr. 1989 Apr;114(4 Pt 1):607–610. doi: 10.1016/s0022-3476(89)80706-1. [DOI] [PubMed] [Google Scholar]
  9. Gibson K. M., Jakobs C., Ogier H., Hagenfeldt L., Eeg-Olofsson K. E., Eeg-Olofsson O., Aksu F., Weber H. P., Rossier E., Vollmer B. Vigabatrin therapy in six patients with succinic semialdehyde dehydrogenase deficiency. J Inherit Metab Dis. 1995;18(2):143–146. doi: 10.1007/BF00711750. [DOI] [PubMed] [Google Scholar]
  10. Gibson K. M., Lee C. F., Chambliss K. L., Kamali V., Francois B., Jaeken J., Jakobs C. 4-Hydroxybutyric aciduria: application of a fluorometric assay to the determination of succinic semialdehyde dehydrogenase activity in extracts of cultured human lymphoblasts. Clin Chim Acta. 1991 Feb 15;196(2-3):219–221. doi: 10.1016/0009-8981(91)90076-o. [DOI] [PubMed] [Google Scholar]
  11. Haan E. A., Brown G. K., Mitchell D., Danks D. M. Succinic semialdehyde dehydrogenase deficiency--a further case. J Inherit Metab Dis. 1985;8(3):99–99. doi: 10.1007/BF01819287. [DOI] [PubMed] [Google Scholar]
  12. Hempel J., Nicholas H., Lindahl R. Aldehyde dehydrogenases: widespread structural and functional diversity within a shared framework. Protein Sci. 1993 Nov;2(11):1890–1900. doi: 10.1002/pro.5560021111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Jakobs C., Bojasch M., Mönch E., Rating D., Siemes H., Hanefeld F. Urinary excretion of gamma-hydroxybutyric acid in a patient with neurological abnormalities. The probability of a new inborn error of metabolism. Clin Chim Acta. 1981 Apr 9;111(2-3):169–178. doi: 10.1016/0009-8981(81)90184-4. [DOI] [PubMed] [Google Scholar]
  14. Jakobs C., Ogier H., Rabier D., Gibson K. M. Prenatal detection of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria) Prenat Diagn. 1993 Feb;13(2):150–150. doi: 10.1002/pd.1970130213. [DOI] [PubMed] [Google Scholar]
  15. Jakobs C., Smit L. M., Kneer J., Michael T., Gibson K. M. The first adult case with 4-hydroxybutyric aciduria. J Inherit Metab Dis. 1990;13(3):341–344. doi: 10.1007/BF01799390. [DOI] [PubMed] [Google Scholar]
  16. Kozak M. Structural features in eukaryotic mRNAs that modulate the initiation of translation. J Biol Chem. 1991 Oct 25;266(30):19867–19870. [PubMed] [Google Scholar]
  17. Krawczak M., Reiss J., Cooper D. N. The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences. Hum Genet. 1992 Sep-Oct;90(1-2):41–54. doi: 10.1007/BF00210743. [DOI] [PubMed] [Google Scholar]
  18. Lennon G., Auffray C., Polymeropoulos M., Soares M. B. The I.M.A.G.E. Consortium: an integrated molecular analysis of genomes and their expression. Genomics. 1996 Apr 1;33(1):151–152. doi: 10.1006/geno.1996.0177. [DOI] [PubMed] [Google Scholar]
  19. Matern D., Lehnert W., Gibson K. M., Korinthenberg R. Seizures in a boy with succinic semialdehyde dehydrogenase deficiency treated with vigabatrin (gamma-vinyl-GABA). J Inherit Metab Dis. 1996;19(3):313–318. doi: 10.1007/BF01799261. [DOI] [PubMed] [Google Scholar]
  20. Trettel F., Malaspina P., Jodice C., Novelletto A., Slaughter C. A., Caudle D. L., Hinson D. D., Chambliss K. L., Gibson K. M. Human succinic semialdehyde dehydrogenase. Molecular cloning and chromosomal localization. Adv Exp Med Biol. 1997;414:253–260. [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES