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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. In particular, several studies have found genetic association and rare variants in the AHI1 gene that are associated with Joubert syndrome. In addition, genetic association between AHI1 and schizophrenia has been seen in a large European sample.

Molecular Function

This gene is apparently required for both cerebellar and cortical development in humans. Mutations in this gene cause specific forms of Joubert syndrome-related disorders. It encodes a modular protein that contains one SH3 motif and seven WD40 repeats

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Association of common variants in the Joubert syndrome gene (AHI1) with autism.
Joubert syndrome-3
ASD
Support
Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene ...
DD, ID, ASD
MCA
Support
Using whole-exome sequencing to identify inherited causes of autism.
ASD
Support
Integrating de novo and inherited variants in 42
ASD
Support
Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.
ASD
Support
Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders.
Joubert syndrome
ID, epilepsy/seizures
Support
Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families.
DD
Support
The contribution of de novo coding mutations to autism spectrum disorder
ASD
Support
DD
Highly Cited
Mutations in the AHI1 gene, encoding jouberin, cause Joubert syndrome with cortical polymicrogyria.
Joubert syndrome-3
Highly Cited
Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome.
Joubert syndrome-3
Recent Recommendation
CC2D2A is mutated in Joubert syndrome and interacts with the ciliopathy-associated basal body protein CEP290.
Recent Recommendation
The Joubert syndrome-associated missense mutation (V443D) in the Abelson-helper integration site 1 (AHI1) protein alters its localization and prote...
Recent Recommendation
Species differences in the expression of Ahi1, a protein implicated in the neurodevelopmental disorder Joubert syndrome, with preferential accumula...
Recent Recommendation
Hypothalamic Ahi1 mediates feeding behavior through interaction with 5-HT2C receptor.
Recent Recommendation
Huntingtin-associated protein 1 interacts with Ahi1 to regulate cerebellar and brainstem development in mice.
Recent Recommendation
Modelling a ciliopathy: Ahi1 knockdown in model systems reveals an essential role in brain, retinal, and renal development.
Recent Recommendation
Genetic basis of Joubert syndrome and related disorders of cerebellar development.
Recent Recommendation
Retinal degeneration and failure of photoreceptor outer segment formation in mice with targeted deletion of the Joubert syndrome gene, Ahi1.
Recent Recommendation
AHI1 is required for photoreceptor outer segment development and is a modifier for retinal degeneration in nephronophthisis.
Recent Recommendation
A large replication study and meta-analysis in European samples provides further support for association of AHI1 markers with schizophrenia.
SCZ

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN008R001a 
 frameshift_variant 
 c.787dup 
 p.Gln263ProfsTer8 
 Familial 
 Both parents 
 Simplex 
 GEN008R002a 
 frameshift_variant 
 c.1190_1191del 
 p.Val397GlyfsTer12 
 Familial 
 Both parents 
 Simplex 
 GEN008R003a 
 missense_variant 
 c.1328T>A 
 p.Val443Asp 
 Familial 
 Both parents 
 Multiplex 
 GEN008R004 
 stop_gained 
 c.1051C>T 
 p.Arg351Ter 
  
  
  
 GEN008R005 
 stop_gained 
 c.1303C>T 
 p.Arg435Ter 
  
  
  
 GEN008R006 
 missense_variant 
 c.1328T>A 
 p.Val443Asp 
  
  
  
 GEN008R007a 
 missense_variant 
 c.2798A>G 
 p.Tyr933Cys 
 Familial 
 Both parents 
 Simplex 
 GEN008R008 
 missense_variant 
 c.3535G>T 
 p.Asp1179Tyr 
 Unknown 
 Not maternal 
  
 GEN008R009 
 missense_variant 
 c.3257A>G 
 p.Glu1086Gly 
 Unknown 
 Not tested 
  
 GEN008R010a 
 missense_variant 
 c.1328T>A 
 p.Val443Asp 
 Familial 
 Both parents 
 Multiplex 
 GEN008R011 
 missense_variant 
 c.1414C>T 
 p.Arg472Trp 
 De novo 
  
 Simplex 
 GEN008R012a 
 frameshift_variant 
 c.910dup 
 p.Thr304AsnfsTer6 
 Familial 
 Both parents 
 Multiplex 
 GEN008R013a 
 stop_gained 
 c.1828C>T 
 p.Arg610Ter 
 Familial 
 Both parents 
 Multiplex 
 GEN008R014 
 splice_site_variant 
 c.3588+1G>A 
  
 Familial 
 Paternal 
 Multiplex (monozygotic twins) 
 GEN008R015 
 stop_gained 
 c.2282C>G 
 p.Ser761Ter 
 Familial 
 Maternal 
 Multiplex 
 GEN008R016 
 stop_gained 
 c.2212C>T 
 p.Arg738Ter 
 Familial 
 Maternal 
 Multiplex 
 GEN008R017 
 synonymous_variant 
 c.3222C>T 
 p.Arg1074%3D 
 De novo 
  
  
 GEN008R018 
 synonymous_variant 
 c.1500C>T 
 p.Tyr500%3D 
 De novo 
  
  
 GEN008R019 
 stop_gained 
 c.2212C>T 
 p.Arg738Ter 
 Familial 
 Maternal 
 Multiplex 
 GEN008R020a 
 splice_site_variant 
 c.1152-1G>C 
  
 Unknown 
  
  
  et al.  

Common

Variant ID
Polymorphism
SNP ID
Allele Change
Residue Change
Population Origin
Population Stage
Author, Year
 GEN008C001 
 intron_variant 
 rs9321501 
 c.3329-1663G>T 
  
 European 
 Discovery 
 GEN008C002 
 intron_variant 
 rs11154801 
 c.2765-6673G>T 
  
 European 
 Discovery 
 GEN008C003 
 upstream_gene_variant 
 rs7750586 
  
 N/A 
 European 
 Discovery 
 GEN008C004 
 upstream_gene_variant 
 rs9647635 
  
  
 European 
 Discovery 
 GEN008C005 
 upstream_gene_variant 
 rs7739635 
  
 N/A 
 European 
 Discovery 
 GEN008C006 
 upstream_gene_variant 
 rs9494332 
  
  
 European 
 Discovery 
 GEN008C007 
 intergenic_variant 
 rs1475069 
  
  
 European 
 Discovery 
 GEN008C008 
 intron_variant 
 rs4896141 
 c.3485+38G>C 
 G 
 AGRE 
 Discovery 
 GEN008C009 
 intron_variant 
 rs11970282 
 c.3589-106A>G;c.3486-106A>G;c.*7-106A>G 
 C 
 AGRE 
 Discovery 
 GEN008C010 
 500B_downstream_variant, 3_prime_UTR_variant 
 rs9494209 
 c.*28G>C;c.*9G>C;c.*37G>C 
 N/A 
 AGRE 
 Discovery 
 GEN008C011 
 500B_downstream_variant, 3_prime_UTR_variant 
 rs1052502 
 c.*218C>T;c.*199C>T;c.*227C>T 
  
 AGRE 
 Discovery 
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
6
Deletion
 1
 
6
Deletion-Duplication
 9
 

Model Summary

Distribution and functioning of Rab8a is regulated by Ahi1, not only affecting cilium formation, but also vesicle transport.

References

Type
Title
Author, Year
Primary
Ahi1, whose human ortholog is mutated in Joubert syndrome, is required for Rab8a localization, ciliogenesis and vesicle trafficking.
Additional
Neuronal Abelson helper integration site-1 (Ahi1) deficiency in mice alters TrkB signaling with a depressive phenotype.
Primary
Neural mechanisms underlying stress resilience in Ahi1 knockout mice: relevance to neuropsychiatric disorders.
Additional
Autism spectrum disorder-like behavior caused by reduced excitatory synaptic transmission in pyramidal neurons of mouse prefrontal cortex

M_AHI1_1_KO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Targeted deletion of exons 3-6 of the Ahi1 gene using homologous recombination.
Allele Type: Targeted (Knock Out)
Strain of Origin: C57BL/6J
Genetic Background: Not Specified
ES Cell Line: Bruce 4
Mutant ES Cell Line: Not Specified
Model Source: Not Specified

M_AHI1_2_CKO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Conditional deletion of exon 2 of Ahi1 using Nestin-Cre, in neuronal, glial and other cell types in the central and peripheral nervous system
Allele Type: Conditional loss-of-function
Strain of Origin: C57BL/6
Genetic Background: Not Specified
ES Cell Line: B6/129
Mutant ES Cell Line: Not Specified
Model Source: Not Specified

M_AHI1_3_KO_HT

Model Type: Genetic
Model Genotype: Heterozygous
Mutation: A gene trap vector containing splice-acceptor sequence upstream of beta-geo reporter gene was introduced into mouse lines, at the Ahi1 locus. Chimeric mice carrying the gene trap vector were crosse with WT mice to get the heterozygotes.
Allele Type: Targeted (Knock Out)
Strain of Origin:
Genetic Background: C57BL/6
ES Cell Line:
Mutant ES Cell Line:
Model Source:

M_AHI1_4_KD

Model Type: Genetic LOF
Model Genotype: Wildtype
Mutation: Knockdown of ahi1 in layer 2/3 pyramidal neurons of the developing mouse prefrontal cortex. pregnant icr mice at e14â??15 were injected intraperitoneally with egfp-pcag plasmid vectors carrying rnai to knockdown the expression of ahi1 pyramidal neurons.
Allele Type: Wildtype
Strain of Origin: ICR
Genetic Background: ICR
ES Cell Line:
Mutant ES Cell Line:
Model Source:

M_AHI1_1_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Protein modification process1
Decreased
Description: Decreased expression of acetylated alpha-tubulin demonstrating reduction in primary cilia
Exp Paradigm: Acetylated alpha-tubulin expression
 Immunohistochemistry
 Unreported
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Emotion, Immune response, Learning & memory, Maternal behavior, Motor phenotype, Neuroanatomy / ultrastructure / cytoarchitecture, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior

M_AHI1_2_CKO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Depression1
Increased
Description: Increased depression demonstrated by increasing immobility in the forced swim test
Exp Paradigm: Forced swim test
 Forced swim test
 7-9 months
Protein expression level evidence1
Decreased
Description: Decreased expression of both ahi1 and hap1 in hypothalamus
Exp Paradigm: Ahi1/hap1 protein expression
 Immunohistochemistry
 Unreported
Protein phosphorylation1
Decreased
Description: Decreased phosphorylation of akt and erk in hypothalamus
Exp Paradigm: Akt/erk protein phosphorylation
 Immunohistochemistry
 Unreported
Protein expression level evidence1
Decreased
Description: Decreased levels of trkb and phosphorylated (p-trkb) in the hypothalamus
Exp Paradigm: Trkb/p-trkb protein expression
 Immunohistochemistry
 Unreported
General characteristics1
 No change
 General observations
 Unreported
General locomotor activity1
 No change
 Open field test
 Unreported
Motor coordination and balance1
 No change
 Accelerating rotarod test
 Unreported
 Not Reported: Circadian sleep/wake cycle, Communications, Immune response, Learning & memory, Maternal behavior, Neuroanatomy / ultrastructure / cytoarchitecture, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior

M_AHI1_3_KO_HT

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Functional magnetic resonance imaging1
Decreased
Description: Ahi1 hets displayed significantly decreased connectivity with the ventral hippocampus and the lateral entorhinal cortex, compared to wild type controls
Exp Paradigm: NA
 Functional magnetic resonance imaging (fmri)-resting state
 8 weeks
Hyperthermia: stress induced1
Decreased
Description: Ahi1 hets displayed a significant drop in body temperature after insertion of a rectal probe, whereas wild type littermates showed a significant rise in temp
Exp Paradigm: The paradigm involved insertion of a rectal probe that causes an autonomic stress response
 Measurement of stress-induced hyperthermia
 2, 4 months
Hormone levels1
Decreased
Description: The levels of corticosterone were lowere in ahi1 heterozygotes compared to wild type littermates.
Exp Paradigm: NA
 Corticosterone measurements
 Unreported
Anxiety1
Decreased
Description: Compared to wild type littermates, ahi1 hets showed less anxiety and spent more time in open arms
Exp Paradigm: NA
 Elevated plus maze test
 2, 4 months
Anxiety1
Decreased
Description: Compared to wild type littermates, ahi1 hets showed less anxiety and spent more time in light chamber
Exp Paradigm: NA
 Light-dark exploration test
 2 months
General characteristics1
 No change
 General observations
 2 months
Size/growth1
 No change
 NA
 2 months
Depression1
 No change
 Forced swim test
 2 months
General locomotor activity1
 No change
 Open field test
 Unreported
Brain morphology1
 No change
 Histology
 2 months
Hearing1
 No change
 Preyer's reflex test
 Unreported
Olfaction1
 No change
 Buried food test
 2 months
Sensorimotor gating1
 No change
 Prepulse inhibition
 2 months
Startle response: acoustic stimulus1
 No change
 Prepulse inhibition
 Unreported
Touch1
 No change
 NA
 Unreported
Vision1
 No change
 Forepaw reaching test
 2 months
Vision1
 No change
 Morris water maze test
 2 months
Social approach1
 No change
 Three-chamber social approach test
 2 months
Social interaction1
 No change
 Reciprocal social interaction test
 2 months
 Not Reported: Circadian sleep/wake cycle, Communications, Immune response, Learning & memory, Maternal behavior, Molecular profile, Physiological parameters, Repetitive behavior, Seizure

M_AHI1_4_KD

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Miniature post synaptic current amplitude: excitatory1
Decreased
Description: Decreased mepsc amplitude at 8-11 weeks; no change in amplitude of mepsc at p16 to p24
 Whole-cell patch clamp
 P16 -P24, 8 -11 weeks
Synaptic transmission: excitatory1
Decreased
Description: Decreased amplitude of evoked epsc
 Whole-cell patch clamp
 P16 -P24, 8 - 11 weeks
EPSP-spike relationship1
Decreased
Description: Decreased slope of epsc amplitude with increased intensity of stimulus
 Whole-cell patch clamp
 P16 -P24, 8 -11 weeks
Synaptic transmission1
Abnormal
Description: Increased i/e ratio
 Whole-cell patch clamp
 P16 -P24, 8 - 11 weeks
Synaptic neuroreceptor ratio (NMDAR/AMPAR) dependent transmission1
Increased
Description: Increased in nmda/ampa ratio
 Whole-cell patch clamp
 2-3 weeks, 8 - 11 weeks
Social approach1
Decreased
Description: Decrease in sociability index measured as ratio of time spent interacting with a novel mouse versus a novel object
 Three-chamber social approach test
 8 - 18 weeks
Social interaction1
Decreased
Description: Decrease in time spent interacting with novel mouse
 Reciprocal social interaction test
 8 - 18 weeks
Social approach1
Decreased
Description: Decrease in time spent sniffing novel mouse
 Partition test
 8 - 18 weeks
Ultrasonic vocalization: Isolation induced1
Decreased
Description: Decrease in duration of calls
 Monitoring ultrasonic vocalizations
 P7
Depression1
Decreased
Description: Decrease in time spent immobile
 Tail suspension test
 8 - 18 weeks
Targeted expression1
Decreased
Description: Egfp positive transfected cells with ahi1 knockdown at postnatal 8â??18 weeks were layer 2/3 pyramidal neurons were located in the pfc, including the dorsolateral prefrontal cortex (dl-pfc), medial prefrontal cortex (mpfc), orbitofrontal cortex (ofc), and anterior cingulate cortex (cgcx)
 Immunohistochemistry
 8 - 18 weeks
Anxiety1
 No change
 Light-dark exploration test
 8 - 18 weeks
Anxiety1
 No change
 Elevated plus maze test
 8 - 18 weeks
Depression1
 No change
 Forced swim test
 8 - 18 weeks
Exploratory activity1
 No change
 Novel object exploration test
 8 - 18 weeks
Cognitive flexibility1
 No change
 Operant conditioning paradigm
 8 - 18 weeks
Spatial working memory1
 No change
 Y-maze test
 8 - 18 weeks
General locomotor activity: Ambulatory activity1
 No change
 Open field test
 8 - 18 weeks
Decay kinetics of miniature post synaptic currents1
 No change
 Whole-cell patch clamp
 8 - 18 weeks
Miniature post synaptic current amplitude: inhibitory1
 No change
 Whole-cell patch clamp
 8 - 18 weeks
Miniature post synaptic current frequency: excitatory1
 No change
 Whole-cell patch clamp
 P16 -P24, 8 -11 weeks
Miniature post synaptic current frequency: inhibitory1
 No change
 Whole-cell patch clamp
 8 - 18 weeks
Miniature post synaptic currents: excitatory1
 No change
 Whole-cell patch clamp
 8 - 18 weeks
Presynaptic function: paired-pulse facilitation1
 No change
 Whole-cell patch clamp
 2-3 weeks
Repetitive digging1
 No change
 Marble-burying test
 8 - 18 weeks
Self grooming1
 No change
 Grooming behavior assessments
 8 - 18 weeks
 Not Reported:





Download AHI1's Cytoscape file

Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
DOCK5 dedicator of cytokinesis 5 80005 Q68DL4 IP; LC-MS/MS
Huttlin EL , et al. 2015
FMR1 fragile X mental retardation 1 2332 G8JLE9 PAR-CLIP; RNA immunoprecipitation (RIP)
Ascano M Jr , et al. 2012
NPHP1 nephronophthisis 1 (juvenile) 4867 O15259 Y2H; IP/WB
Eley L , et al. 2008
Arx aristaless related homeobox 11878 O35085 ChIP-qPCR
Quill ML , et al. 2011
Hap1 huntingtin-associated protein 1 15114 O35668 GST; IP/WB
Sheng G , et al. 2008
Rab8a RAB8A, member RAS oncogene family 17274 P55258 IP/WB
Hsiao YC , et al. 2009

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