A novel ALDH5A1 mutation is associated with succinic semialdehyde dehydrogenase deficiency and severe intellectual disability in an Iranian family.

Abstract

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a disorder of the catabolism of the neurotransmitter gamma-aminobutyric acid (GABA) with a very variable clinical phenotype ranging from mild intellectual disability to severe neurological defects. We report here on a large Iranian family with four affected patients presenting with severe intellectual disability, developmental delay and generalized tonic-clonic seizures. Molecular genetic analysis revealed a missense mutation c.901A>G (p.K301E, RefSeq number NM_001080) in ALDH5A1 co-segregating with the disease in the family. The missense mutation affects an amino acid residue that is highly conserved across the animal kingdom. Protein modeling showed that p.K301E most likely leads to a loss of NAD(+) binding and a predicted decrease in the free energy by 6.67 kcal/mol furthermore suggests a severe destabilization of the protein. In line with these in silico observations, no SSADH enzyme activity could be detected in patient lymphoblasts.

• Authors: Lucia Püttmann, Henning Stehr, Masoud Garshasbi, Hao Hu, Kimia Kahrizi, Bettina Lipkowitz, Payman Jamali, Andreas Tzschach, Hossein Najmabadi, Hans-Hilger Ropers, Luciana Musante, Andreas W Kuss
• Journal: American journal of medical genetics. Part A (Am J Med Genet A) Vol. 161A Issue 8 Pg. 1915-22 (Aug 2013) ISSN: 1552-4833 [Electronic] United States
• PMID: 23825041 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Wiley Periodicals, Inc.

Chemical References

• DNA
• ALDH5A1 protein, human
• Succinate-Semialdehyde Dehydrogenase
• 1-Pyrroline-5-Carboxylate Dehydrogenase
• ALDH4A1 protein, human

Topics

• 1-Pyrroline-5-Carboxylate Dehydrogenase (genetics)
• Adult
• Amino Acid Metabolism, Inborn Errors (genetics)
• DNA (analysis, genetics)
• Developmental Disabilities
• Humans
• Intellectual Disability (genetics)
• Iran
• Male
• Mutation, Missense (genetics)
• Pedigree
• Polymerase Chain Reaction
• Polymorphism, Single Nucleotide
• Succinate-Semialdehyde Dehydrogenase (blood, deficiency, genetics)
• Young Adult