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Relevance to Autism

This gene has been associated with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism.

Molecular Function

The encoded protein is a mitochondrial NAD(+)-dependent succinic semialdehyde dehydrogenase.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Clinical spectrum of succinic semialdehyde dehydrogenase deficiency.
SSADH deficiency
Autism
Support
Synaptic, transcriptional and chromatin genes disrupted in autism.
ASD
Support
Case Report: Whole Exome Sequencing Revealed Disease-Causing Variants in Two Genes in a Patient With Autism Spectrum Disorder, Intellectual Disability, Hyperactivity, Sleep and Gastrointestinal Distur
ASD
DD, ID
Support
Clinical and molecular outcomes from the 5-Year natural history study of SSADH Deficiency, a model metabolic neurodevelopmental disorder
Succinic semialdehyde dehydrogenase deficiency
Support
Bi-allelic Mutations in ALDH5A1 is associated with succinic semialdehyde dehydrogenase deficiency and severe intellectual disability
SSADH deficiency
ASD, ADHD, DD, ID, epilepsy/seizures
Support
The continuously evolving phenotype of succinic semialdehyde dehydrogenase deficiency
Succinic semialdehyde dehydrogenase deficiency
Support
Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.
ASD
Support
ALDH5A1-deficient iPSC-derived excitatory and inhibitory neurons display cell type specific alterations
Succinic semialdehyde dehydrogenase deficiency
Support
Two exon-skipping mutations as the molecular basis of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria).
SSADH deficiency
Autism
Support
Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders.
SSADH deficiency
ID, hypotonia
Support
Neurometabolic profiles of autism spectrum disorder patients with genetic variants in specific neurotransmission and synaptic genes
ASD
Support
SSADH deficiency possibly associated with enzyme activity-reducing SNPs.
SSADH deficiency
DD, ASD, epilepsy
Support
Integrating de novo and inherited variants in 42
ASD
Support
Rare Variant Burden and Behavioral Phenotypes in Children with Autism in Slovakia
ASD
Support
The contribution of de novo coding mutations to autism spectrum disorder
ASD
Support
Trio-based exome sequencing reveals a high rate of the de novo variants in intellectual disability
ID
Support
Exome Study of Single Nucleotide Variations in Patients with Syndromic and Non-Syndromic Autism Reveals Potential Candidate Genes for Diagnostics and Novel Single Nucleotide Variants
ASD
DD, epilepsy/seizures
Highly Cited
Distribution of messenger RNAs for aldehyde dehydrogenase 1, aldehyde dehydrogenase 2, and aldehyde dehydrogenase 5 in human tissues.
Recent Recommendation
Testicular germ cell tumors. Clinically relevant pathologic findings.
Recent Recommendation
Succinic semialdehyde dehydrogenase deficiency (SSADH) (4-hydroxybutyric aciduria, gamma-hydroxybutyric aciduria).
Recent Recommendation
The neuropsychological profile of SSADH deficiency, a neurotransmitter disorder of GABA metabolism
SSADH deficiency
ASD

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN009R001a 
 splice_site_variant 
 G>T 
  
 Familial 
 Both parents 
 Extended multiplex 
 GEN009R002a 
 splice_site_variant 
 G>A 
  
 Familial 
 Both parents 
 Simplex 
 GEN009R003 
 missense_variant 
 c.1145G>A 
 p.Arg382His 
 De novo 
  
 Simplex 
 GEN009R004 
 missense_variant 
 c.664G>A 
 p.Gly222Ser 
 De novo 
  
 Simplex 
 GEN009R005 
 missense_variant 
 c.1586G>A 
 p.Gly529Glu 
 Familial 
 Paternal 
 Simplex 
 GEN009R006a 
 splice_site_variant 
 c.1402+1G>T 
  
 Familial 
 Both parents 
 Multiplex 
 GEN009R007 
 splice_site_variant 
 c.1213-2A>C 
  
 Familial 
 Maternal 
 Simplex 
 GEN009R008 
 missense_variant 
 c.638G>A 
 p.Arg213Gln 
 Familial 
 Maternal 
 Simplex 
 GEN009R009a 
 missense_variant 
 c.1321G>A 
 p.Gly441Arg 
 Familial 
 Both parents 
 Multiplex 
 GEN009R010a 
 stop_gained 
 c.612G>A 
 p.Trp204Ter 
 Familial 
 Maternal 
 Simplex 
 GEN009R010b 
 missense_variant 
 c.538C>T 
 p.His180Tyr 
 Familial 
 Paternal 
 Simplex 
 GEN009R011a 
 missense_variant 
 c.698C>T 
 p.Thr233Met 
 Familial 
 Both parents 
  
 GEN009R012 
 missense_variant 
 c.74G>A 
 p.Arg25His 
 De novo 
  
 Simplex 
 GEN009R013 
 stop_gained 
 c.612G>A 
 p.Trp204Ter 
 Familial 
 Paternal 
 Multiplex 
 GEN009R014 
 frameshift_variant 
 c.858del 
 p.Asp287IlefsTer27 
 Familial 
 Maternal 
 Multiplex 
 GEN009R015a 
 frameshift_variant 
 c.804dup 
 p.Val269CysfsTer19 
 Familial 
 Paternal 
  
 GEN009R015b 
 missense_variant 
 c.1265G>A 
 p.Gly422Asp 
 Familial 
 Maternal 
  
 GEN009R016 
 stop_gained 
 c.1234C>T 
 p.Arg412Ter 
 Unknown 
  
 Unknown 
 GEN009R017 
 missense_variant 
 c.515G>A 
 p.Arg172His 
 Unknown 
  
  

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
6
Deletion-Duplication
 11
 
6
Deletion-Duplication
 29
 
6
Deletion
 1
 
6
Deletion
 1
 

Model Summary

Mice display ataxia, develop generalized seizures leading to rapid death,increased amounts of GHB and total GABA in urine, brain and liver homogenates and detected significant gliosis in the hippocampus of KO mice. These findings provide insight into pathomechanisms and may have therapeutic relevance for the human SSADH deficiency disease and GHB overdose and toxicity.

References

Type
Title
Author, Year
Primary
Pharmacologic rescue of lethal seizures in mice deficient in succinate semialdehyde dehydrogenase.

M_ALDH5A1_1_KO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Targeted disruption of part of exon 7 of the Aldh5a1 gene which contains the active site using gene targeting.
Allele Type: Targeted (Knock Out)
Strain of Origin: C57BL6/129 SV
Genetic Background: Not Specified
ES Cell Line: 129/Sv
Mutant ES Cell Line: Not Specified
Model Source: Not Specified

M_ALDH5A1_2_KO_HT

Model Type: Genetic
Model Genotype: Heterozygous
Mutation: Targeted disruption of part of exon 7 of the Aldh5a1 gene which contains the active site using gene targeting.
Allele Type: Targeted (Knock Out)
Strain of Origin: C57BL6/129 SV
Genetic Background: Not Specified
ES Cell Line: 129/Sv
Mutant ES Cell Line: Not Specified
Model Source: Not Specified

M_ALDH5A1_1_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Ataxia1
Increased
Description: Manifestation of atactic locomotion
Exp Paradigm: General visual observation
 General observations
 Unreported
Seizures1
Increased
Description: Increased survival and absence of tonic-clonic convulsions in response to vigabatrin (vgb) administration
Exp Paradigm: Survival curve
 Survival analysis
 Unreported
Seizures1
Increased
Description: Increased spasms and tonic-clonic seizures leading to status epilepticus
Exp Paradigm: General observations
 General observations
 Unreported
Seizures1
Increased
Description: Increased survival in response to gababr antagonist cgp 35348
Exp Paradigm: Survival curve
 Survival analysis
 Unreported
Mortality/lethality1
Increased
Description: Increased lethality
Exp Paradigm: General observations
 General observations
 P16-p22
Size/growth1
Decreased
Description: Decreased body weight
Exp Paradigm: General observations
 General observations
 Unreported
Astrogliosis1
Increased
Description: Increased astrogliosis in dorsal hippocampal commissure, stria terminalis, inferior colliculus and dorsolateral medulla
Exp Paradigm: Immunohistochemical staining for glial fibrillary acidic protein (gfap) of paraformaldehyde-fixed brain slices
 Immunohistochemistry
 Unreported
Metabolite level quantification1
Increased
Description: Increased ghb and total gaba protein levels in brain and liver
Exp Paradigm: Metabolite quantification
 Gas chromatography-mass spectrometry (gc-ms)
 Unreported
Enzyme activity1
Decreased
Description: Absence of ssadh enzyme activity in brain, liver, heart, and kidney
Exp Paradigm: Ssadh enzyme activity
 Enzyme assay
 Unreported
Metabolite level quantification1
 No change
 Gas chromatography-mass spectrometry (gc-ms)
 Unreported
Brain morphology1
 No change
 Histology
 P13-p18
 Not Reported: Circadian sleep/wake cycle, Communications, Emotion, Learning & memory, Maternal behavior, Neurophysiology, Physiological parameters, Repetitive behavior, Sensory, Social behavior

M_ALDH5A1_2_KO_HT

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Enzyme activity1
Decreased
Description: Reduced ssadh enzyme activity in brain, liver, heart, and kidney
Exp Paradigm: Ssadh enzyme activity
 Enzyme assay
 Unreported
Size/growth1
 No change
 General observations
 Unreported
Astrogliosis1
 No change
 Immunohistochemistry
 Unreported
Metabolite level quantification1
 No change
 Gas chromatography-mass spectrometry (gc-ms)
 Unreported
 Not Reported: Circadian sleep/wake cycle, Communications, Emotion, Learning & memory, Maternal behavior, Motor phenotype, Neuroanatomy / ultrastructure / cytoarchitecture, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior





Download ALDH5A1's Cytoscape file

Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
C17ORF90 oxidoreductase-like domain containing 1 339229 Q5BKU9 IP; LC-MS/MS
Huttlin EL , et al. 2015
C1ORF85 GAN 112770 Q8WWB7 IP; LC-MS/MS
Huttlin EL , et al. 2015
FGL1 Fibrinogen-like protein 1 2267 Q08830 IP; LC-MS/MS
Huttlin EL , et al. 2015
FMR1 fragile X mental retardation 1 2332 G8JLE9 PAR-CLIP
Ascano M Jr , et al. 2012
GATC Glutamyl-tRNA(Gln) amidotransferase subunit C, mitochondrial 283459 O43716 IP; LC-MS/MS
Huttlin EL , et al. 2015
MAGEA11 melanoma antigen family A11 4110 G5E962 Y2H
Corominas R , et al. 2014
MRPL50 mitochondrial ribosomal protein L50 54534 Q8N5N7 IP; LC-MS/MS
Huttlin EL , et al. 2015
ABAT 4-aminobutyrate aminotransferase 18 P80147 Affinity chromatography
Hearl WG and Churchich JE 1984

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