AHI1Abelson helper integration site 1
Autism Reports / Total Reports
6 / 23Rare Variants / Common Variants
21 / 9Aliases
AHI1, ORF1, AHI-1, JBTS3, FLJ14023, FLJ20069, dJ71N10.1, DKFZp686J1653Associated Syndromes
Joubert syndrome-3, Joubert syndromeChromosome Band
6q23.3Associated Disorders
ID, ASD, EPSRelevance 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
SFARI Genomic Platforms
Reports related to AHI1 (23 Reports)
| # | Type | Title | Author, Year | Autism Report | Associated Disorders |
|---|---|---|---|---|---|
| 1 | Highly Cited | Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome | Ferland RJ , et al. (2004) | No | - |
| 2 | Highly Cited | Mutations in the AHI1 gene, encoding jouberin, cause Joubert syndrome with cortical polymicrogyria | Dixon-Salazar T , et al. (2004) | No | - |
| 3 | Recent Recommendation | Genetic basis of Joubert syndrome and related disorders of cerebellar development | Louie CM and Gleeson JG (2005) | No | - |
| 4 | Recent Recommendation | Huntingtin-associated protein 1 interacts with Ahi1 to regulate cerebellar and brainstem development in mice | Sheng G , et al. (2008) | No | - |
| 5 | Primary | Association of common variants in the Joubert syndrome gene (AHI1) with autism | Alvarez Retuerto AI , et al. (2008) | No | ASD |
| 6 | Recent Recommendation | Species differences in the expression of Ahi1, a protein implicated in the neurodevelopmental disorder Joubert syndrome, with preferential accumulation to stigmoid bodies | Doering JE , et al. (2008) | No | - |
| 7 | Recent Recommendation | CC2D2A is mutated in Joubert syndrome and interacts with the ciliopathy-associated basal body protein CEP290 | Gorden NT , et al. (2008) | No | - |
| 8 | Recent Recommendation | A large replication study and meta-analysis in European samples provides further support for association of AHI1 markers with schizophrenia | Ingason A , et al. (2010) | No | - |
| 9 | Recent Recommendation | AHI1 is required for photoreceptor outer segment development and is a modifier for retinal degeneration in nephronophthisis | Louie CM , et al. (2010) | No | - |
| 10 | Recent Recommendation | Retinal degeneration and failure of photoreceptor outer segment formation in mice with targeted deletion of the Joubert syndrome gene, Ahi1 | Westfall JE , et al. (2010) | No | - |
| 11 | Recent Recommendation | Modelling a ciliopathy: Ahi1 knockdown in model systems reveals an essential role in brain, retinal, and renal development | Simms RJ , et al. (2011) | No | - |
| 12 | Recent Recommendation | Hypothalamic Ahi1 mediates feeding behavior through interaction with 5-HT2C receptor | Wang H , et al. (2011) | No | - |
| 13 | Support | Using whole-exome sequencing to identify inherited causes of autism | Yu TW , et al. (2013) | Yes | - |
| 14 | Recent Recommendation | The Joubert syndrome-associated missense mutation (V443D) in the Abelson-helper integration site 1 (AHI1) protein alters its localization and protein-protein interactions | Tuz K , et al. (2013) | No | - |
| 15 | Support | Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene panel | Brett M , et al. (2014) | Yes | MCA |
| 16 | Support | The contribution of de novo coding mutations to autism spectrum disorder | Iossifov I et al. (2014) | Yes | - |
| 17 | Support | Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families | Alazami AM , et al. (2015) | No | - |
| 18 | Support | Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders | Reuter MS , et al. (2017) | No | ID, epilepsy/seizures |
| 19 | Support | Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks | Ruzzo EK , et al. (2019) | Yes | - |
| 20 | Support | - | Zhou X et al. (2022) | Yes | - |
| 21 | Support | - | Cirnigliaro M et al. (2023) | Yes | - |
| 22 | Support | - | Karthika Ajit Valaparambil et al. () | No | - |
| 23 | Support | - | Axel Schmidt et al. (2024) | No | - |
Rare Variants (21)
| Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Parental Transmission | Family Type | PubMed ID | Author, Year |
|---|---|---|---|---|---|---|---|---|
| c.1051C>T | p.Arg351Ter | stop_gained | - | - | - | 15322546 | Ferland RJ , et al. (2004) | |
| c.1303C>T | p.Arg435Ter | stop_gained | - | - | - | 15322546 | Ferland RJ , et al. (2004) | |
| c.1328T>A | p.Val443Asp | missense_variant | - | - | - | 15322546 | Ferland RJ , et al. (2004) | |
| c.1500C>T | p.Tyr500%3D | synonymous_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.3222C>T | p.Arg1074%3D | synonymous_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.1148A>G | p.Asp383Gly | missense_variant | Unknown | - | - | 39039281 | Axel Schmidt et al. (2024) | |
| c.1152-1G>C | - | splice_site_variant | Unknown | - | - | 37943464 | Karthika Ajit Valaparambil et al. () | |
| c.1414C>T | p.Arg472Trp | missense_variant | De novo | - | Simplex | 25363768 | Iossifov I et al. (2014) | |
| c.3257A>G | p.Glu1086Gly | missense_variant | Unknown | Not tested | - | 24690944 | Brett M , et al. (2014) | |
| c.3535G>T | p.Asp1179Tyr | missense_variant | Unknown | Not maternal | - | 24690944 | Brett M , et al. (2014) | |
| c.2212C>T | p.Arg738Ter | stop_gained | Familial | Maternal | Multiplex | 31398340 | Ruzzo EK , et al. (2019) | |
| c.2282C>G | p.Ser761Ter | stop_gained | Familial | Maternal | Multiplex | 31398340 | Ruzzo EK , et al. (2019) | |
| c.2798A>G | p.Tyr933Cys | missense_variant | Familial | Both parents | Simplex | 23352163 | Yu TW , et al. (2013) | |
| c.2212C>T | p.Arg738Ter | stop_gained | Familial | Maternal | Multiplex | 37506195 | Cirnigliaro M et al. (2023) | |
| c.1828C>T | p.Arg610Ter | stop_gained | Familial | Both parents | Multiplex | 28097321 | Reuter MS , et al. (2017) | |
| c.1328T>A | p.Val443Asp | missense_variant | Familial | Both parents | Multiplex | 25558065 | Alazami AM , et al. (2015) | |
| c.1328T>A | p.Val443Asp | missense_variant | Familial | Both parents | Multiplex | 15467982 | Dixon-Salazar T , et al. (2004) | |
| c.910dup | p.Thr304AsnfsTer6 | frameshift_variant | Familial | Both parents | Multiplex | 28097321 | Reuter MS , et al. (2017) | |
| c.3588+1G>A | - | splice_site_variant | Familial | Paternal | Multiplex (monozygotic twins) | 31398340 | Ruzzo EK , et al. (2019) | |
| c.787dup | p.Gln263ProfsTer8 | frameshift_variant | Familial | Both parents | Simplex | 15467982 | Dixon-Salazar T , et al. (2004) | |
| c.1190_1191del | p.Val397GlyfsTer12 | frameshift_variant | Familial | Both parents | Simplex | 15467982 | Dixon-Salazar T , et al. (2004) |
Common Variants (9)
| Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Paternal Transmission | Family Type | PubMed ID | Author, Year |
|---|---|---|---|---|---|---|---|---|
| c.3589-106A>G;c.3486-106A>G;c.*7-106A>G | C | intron_variant | - | - | - | 18782849 | Alvarez Retuerto AI , et al. (2008) | |
| c.*28G>C;c.*9G>C;c.*37G>C | N/A | 500B_downstream_variant, 3_prime_UTR_variant | - | - | - | 18782849 | Alvarez Retuerto AI , et al. (2008) | |
| c.*218C>T;c.*199C>T;c.*227C>T | - | 500B_downstream_variant, 3_prime_UTR_variant | - | - | - | 18782849 | Alvarez Retuerto AI , et al. (2008) | |
| - | - | intergenic_variant | - | - | - | 20071346 | Ingason A , et al. (2010) | |
| - | - | upstream_gene_variant | - | - | - | 20071346 | Ingason A , et al. (2010) | |
| - | N/A | upstream_gene_variant | - | - | - | 20071346 | Ingason A , et al. (2010) | |
| c.2765-6673G>T | - | intron_variant | - | - | - | 20071346 | Ingason A , et al. (2010) | |
| c.3329-1663G>T | - | intron_variant | - | - | - | 20071346 | Ingason A , et al. (2010) | |
| c.3485+38G>C | G | intron_variant | - | - | - | 18782849 | Alvarez Retuerto AI , et al. (2008) |
SFARI Gene score
S
Syndromic
Selected as a candidate gene based on its involvement in Joubert Syndrome. Single association study with significant results (PMID: 18782849), and also reasonably good evidence for a role in schizophrenia (PMID: 20371615).
Score Delta: Score remained at S
criteria met
See SFARI Gene'scoring criteriaThe syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."
10/1/2019
S
S
Score remained at S
New Scoring Scheme
Description
Selected as a candidate gene based on its involvement in Joubert Syndrome. Single association study with significant results (PMID: 18782849), and also reasonably good evidence for a role in schizophrenia (PMID: 20371615).
Reports Added
[New Scoring Scheme]7/1/2019
S
S
Score remained at S
Description
Selected as a candidate gene based on its involvement in Joubert Syndrome. Single association study with significant results (PMID: 18782849), and also reasonably good evidence for a role in schizophrenia (PMID: 20371615).
1/1/2017
S
S
Score remained at S
Description
Selected as a candidate gene based on its involvement in Joubert Syndrome. Single association study with significant results (PMID: 18782849), and also reasonably good evidence for a role in schizophrenia (PMID: 20371615).
1/1/2016
S
S
Score remained at S
Description
Selected as a candidate gene based on its involvement in Joubert Syndrome. Single association study with significant results (PMID: 18782849), and also reasonably good evidence for a role in schizophrenia (PMID: 20371615).
Reports Added
[Using whole-exome sequencing to identify inherited causes of autism.2013] [Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families.2015] [Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene ...2014] [Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome.2004] [Mutations in the AHI1 gene, encoding jouberin, cause Joubert syndrome with cortical polymicrogyria.2004] [Association of common variants in the Joubert syndrome gene (AHI1) with autism.2008] [A large replication study and meta-analysis in European samples provides further support for association of AHI1 markers with schizophrenia.2010] [Genetic basis of Joubert syndrome and related disorders of cerebellar development.2005] [Huntingtin-associated protein 1 interacts with Ahi1 to regulate cerebellar and brainstem development in mice.2008] [Species differences in the expression of Ahi1, a protein implicated in the neurodevelopmental disorder Joubert syndrome, with preferential accumula...2008] [CC2D2A is mutated in Joubert syndrome and interacts with the ciliopathy-associated basal body protein CEP290.2008] [AHI1 is required for photoreceptor outer segment development and is a modifier for retinal degeneration in nephronophthisis.2010] [Retinal degeneration and failure of photoreceptor outer segment formation in mice with targeted deletion of the Joubert syndrome gene, Ahi1.2010] [Modelling a ciliopathy: Ahi1 knockdown in model systems reveals an essential role in brain, retinal, and renal development.2011] [Hypothalamic Ahi1 mediates feeding behavior through interaction with 5-HT2C receptor.2011] [The Joubert syndrome-associated missense mutation (V443D) in the Abelson-helper integration site 1 (AHI1) protein alters its localization and prote...2013] [The contribution of de novo coding mutations to autism spectrum disorder2014]1/1/2015
S
S
Score remained at S
Description
Selected as a candidate gene based on its involvement in Joubert Syndrome. Single association study with significant results (PMID: 18782849), and also reasonably good evidence for a role in schizophrenia (PMID: 20371615).
4/1/2014
No data
S
Score remained at S
Description
Selected as a candidate gene based on its involvement in Joubert Syndrome. Single association study with significant results (PMID: 18782849), and also reasonably good evidence for a role in schizophrenia (PMID: 20371615).
Krishnan Probability Score
Score 0.53783166109253
Ranking 1465/25841 scored genes
[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning
approach on a human brain-specific gene network. The method was first presented in Nat
Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed
in column G of supplementary table 3 (see:
http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser,
with the ability to view networks of associated ASD risk genes, can be found at
asd.princeton.edu.
ExAC Score
Score 3.2566334101061E-14
Ranking 17562/18225 scored genes
[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has
been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by
Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at
exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of-
function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of-
function mutations in autism in such a gene would be more likely to confer risk. For a full list of
pLI scores see:
ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle
aned_exac_nonTCGA_z_pli_rec_null_data.txt
Sanders TADA Score
Score 0.93401921963093
Ranking 12442/18665 scored genes
[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013),
and is a statistic that integrates evidence from both de novo and transmitted mutations.
It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233
(2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper
(the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Zhang D Score
Score 0.3382102411638
Ranking 2160/20870 scored genes
[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures),
or D score, was developed to combine evidence from de novo loss-of- function mutation with
evidence from cell-type- specific gene expression in the mouse brain (specifically translational
profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with
positive D scores are more likely to be associated with autism risk, with higher-confidence genes
having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204-
215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in
supplementary table 2 from that paper.
External PIN Data
Interactome
- Protein Binding
- DNA Binding
- RNA Binding
- Protein Modification
- Direct Regulation
- ASD-Linked Genes
Interaction Table
| Interactor Symbol | Interactor Name | Interactor Organism | Interactor Type | Entrez ID | Uniprot ID |
|---|---|---|---|---|---|
| Arx | aristaless related homeobox | Mouse | DNA Binding | 11878 | O35085 |
| DOCK5 | dedicator of cytokinesis 5 | Human | Protein Binding | 80005 | Q68DL4 |
| Hap1 | huntingtin-associated protein 1 | Mouse | Protein Binding | 15114 | O35668 |
| NPHP1 | nephronophthisis 1 (juvenile) | Human | Protein Binding | 4867 | O15259 |
| Rab8a | RAB8A, member RAS oncogene family | Mouse | Protein Binding | 17274 | P55258 |