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A novel ALDH5A1 mutation is associated with succinic semialdehyde dehydrogenase deficiency and severe intellectual disability in an Iranian family
Author(s) -
Püttmann Lucia,
Stehr Henning,
Garshasbi Masoud,
Hu Hao,
Kahrizi Kimia,
Lipkowitz Bettina,
Jamali Payman,
Tzschach Andreas,
Najmabadi Hossein,
Ropers HansHilger,
Musante Luciana,
Kuss Andreas W.
Publication year - 2013
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.36030
Subject(s) - missense mutation , intellectual disability , genetics , mutation , valine , catabolism , biochemistry , biology , medicine , amino acid , endocrinology , chemistry , enzyme , gene
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. © 2013 Wiley Periodicals, Inc.