Repository of Research and Investigative Information

Repository of Research and Investigative Information

Ilam University of Medical Sciences

Bi-allelic Mutations in ALDH5A1 is associated with succinic semialdehyde dehydrogenase deficiency and severe intellectual disability

Mon Dec 5 13:41:53 2022

(2020) Bi-allelic Mutations in ALDH5A1 is associated with succinic semialdehyde dehydrogenase deficiency and severe intellectual disability. Gene. p. 144918. ISSN 1879-0038 (Electronic) 0378-1119 (Linking)

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Official URL: https://www.ncbi.nlm.nih.gov/pubmed/32621952

Abstract

Homozygous mutations of ALDH5A1 have been reportedly associated with Succinic semialdehyde dehydrogenase deficiency (SSADHD) that affects gamma-aminobutyric acid (GABA) catabolism and evinces a wide range of clinical phenotype from mild intellectual disability to severe neurodegenerative disorders. We report clinical and molecular data of a Lor family with 2 affected members presenting with severe intellectual disability, developmental delay, and generalized tonic-clonic seizures. A comprehensive genetic study that included whole-exome sequencing identified a homozygous missense substitution (NM001080:c.G1321A:p.G441R) in ALDH5A1 (Aldehyde Dehydrogenase 5 Family Member A1) gene, consistent with clinical phenotype in the patients and co-segregating with the disease in the family. The non-synonymous mutation, p.G441R, affects a highly conserved amino acid residue, which is expected to cause a severe destabilization of the enzyme. Protein modeling demonstrated an impairment of the succinic semialdehyde (SSA) binding tunnel accessibility, and the anticipation of the protein folding stability and dynamics was a decrease in the free energy by 4.02 kcal/mol. Consistent with these in silico findings, excessive gamma -hydroxybutyrate (GHB) could be detected in patients' urine as the byproduct of the GABA pathway. SSADHD, Succinic semialdehyde dehydrogenase deficiency; GABA, gamma-aminobutyric acid; ALDH5A1, Aldehyde Dehydrogenase 5 Family Member A1; GHB, gamma -hydroxybutyrate; SSA, succinic semi aldehyde; WISC, Wechsler Intelligence Scale for Children; CNS, central nervous system ; EEG, electroencephalography; EEEF, empirical effective energy functions; ASD, autism spectrum disorder; ADHD, attention deficit hyperactivity disorder; IQ, intelligence quotient; EMG, electromyography; NCV, nerve conduction velocity; CP, cerebral palsy.

Item Type: Article
Creators:
CreatorsEmail
Fattahi, M.UNSPECIFIED
Bushehri, A.UNSPECIFIED
Alavi, A.UNSPECIFIED
Asghariazar, V.UNSPECIFIED
Nozari, A.UNSPECIFIED
Ghasemi Firouzabadi, S.UNSPECIFIED
Motamedian Dehkordi, P.UNSPECIFIED
Javid, M.UNSPECIFIED
Farajzadeh Valiliou, S.UNSPECIFIED
Karimian, J.UNSPECIFIED
Behjati, F.UNSPECIFIED
Keywords: Aldh5a1 Ngs Ssadhd Whole-exome sequencing intellectual disability
Divisions:
Page Range: p. 144918
Journal or Publication Title: Gene
Journal Index: Pubmed
Identification Number: https://doi.org/10.1016/j.gene.2020.144918
ISSN: 1879-0038 (Electronic) 0378-1119 (Linking)
Depositing User: مهندس مهدی شریفی
URI: http://eprints.medilam.ac.ir/id/eprint/3125

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