Mutational spectrum of the succinate semialdehyde dehydrogenase (ALDH5A1) gene and functional analysis of 27 novel disease-causing mutations in patients with SSADH deficiency

Authors

  • Shinjiro Akaboshi,

    1. Departments of Molecular and Medical Genetics and Pediatrics, Oregon Health and Science University, Portland, Oregon
    2. Division of Child Neurology, Institute of Neurological Sciences, Tottori University, Tottori, Japan
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    • Shinjiro Akaboshi and Boris M. Hogema contributed equally to this work.

  • Boris M. Hogema,

    1. Departments of Molecular and Medical Genetics and Pediatrics, Oregon Health and Science University, Portland, Oregon
    2. Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands
    3. Department of Biochemistry, Erasmus University Medical Center Rotterdam, the Netherlands
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    • Shinjiro Akaboshi and Boris M. Hogema contributed equally to this work.

  • Andrea Novelletto,

    1. Department of Cell Biology, University of Calabria, Rende, Italy
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  • Patrizia Malaspina,

    1. Department of Biology, “Tor Vergata” University of Rome, Rome, Italy
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  • Gajja S. Salomons,

    1. Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands
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  • George D. Maropoulos,

    1. Department of Biochemistry, General Hospital of Athens, ‘Laiko,’ Greece
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  • Cornelis Jakobs,

    1. Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands
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  • Markus Grompe,

    1. Departments of Molecular and Medical Genetics and Pediatrics, Oregon Health and Science University, Portland, Oregon
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  • K. Michael Gibson

    Corresponding author
    1. Departments of Molecular and Medical Genetics and Pediatrics, Oregon Health and Science University, Portland, Oregon
    • FACMG, Department of Molecular and Medical Genetics, Biochemical Genetics Laboratory, Oregon Health and Science University, Mail Code MP-350, 2525 SW 3rd Avenue, Suite 350, Portland, OR 97201
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  • Communicated by Johannes Zschocke

Abstract

Succinate semialdehyde dehydrogenase (SSADH; ALDH5A1) deficiency, a rare metabolic disorder that disrupts the normal degradation of GABA, gives rise to a highly heterogeneous neurological phenotype ranging from mild to very severe. The nature of the mutation has so far been reported in patients from six families world wide and eight different mutations were described. Here we report the mutational spectrum in 48 additional unrelated families of different geographic origin. We detected 27 novel mutations at the cDNA level, of which 26 could be attributed to changes at the genomic level. Furthermore, six mutations were detected that did not strongly affect SSADH activity when expressed in HEK 293 cells and are considered nonpathogenic allelic variants. Twenty of the mutations were only found in one family. The spectrum of disease-causing mutations from all patients sequenced thus far consists of 25 point mutations, four small insertions, and five small deletions. Seven of these mutations affect splice junctions, seven are nonsense mutations, and 12 are missense mutations. Although there were no mutational hotspots or prevalent mutations responsible for a significant number of cases, 14 out of 37 (38%) of the missense alleles were present in exon 4 or 5. With one exception, the missense mutations we consider to be causative of SSADH deficiency reduced the SSADH activity to less than 5% of the normal activity in our in vitro expression system. This indicates that residual expression is not likely to be an important factor contributing to the large phenotypic differences observed among different families and even among siblings, suggesting that other modifying factors are of great importance in disease pathology. Hum Mutat 22:442–450, 2003. © 2003 Wiley-Liss, Inc.

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