Human Gene Module / Chromosome 5 / HOMER1

HOMER1Homer homolog 1 (Drosophila)

Score
4
Minimal Evidence Criteria 4.1
Autism Reports / Total Reports
2 / 5
Rare Variants / Common Variants
8 / 0
Aliases
HOMER1, HOMER,  HOMER1A,  HOMER1B,  HOMER1C,  SYN47,  Ves-1
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Functional
Chromosome Band
5q14.1
Associated Disorders
-
Relevance to Autism

Seven rare variants (minor allele frequency < 1%) in the HOMER1 gene were identified in a cohort of 290 non-syndromic ASD cases; none of these variants were observed in 300 ethnically matched controls. Four of the variants in the HOMER1 gene co-segregated with ASD in multiplex families (Kelleher III et al., 2012).

Molecular Function

This gene encodes a member of the homer family of dendritic proteins. Members of this family regulate group 1 metabotrophic glutamate receptor function.

Reports related to HOMER1 (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Recent Recommendation Disrupted Homer scaffolds mediate abnormal mGluR5 function in a mouse model of fragile X syndrome. Ronesi JA , et al. (2012) No -
2 Primary High-throughput sequencing of mGluR signaling pathway genes reveals enrichment of rare variants in autism. Kelleher RJ 3rd , et al. (2012) Yes -
3 Recent Recommendation Impairment of fragile X mental retardation protein-metabotropic glutamate receptor 5 signaling and its downstream cognates ras-related C3 botulinum... Fatemi SH , et al. (2013) Yes -
4 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) No -
5 Recent recommendation Overexpression of Homer1a in the basal and lateral amygdala impairs fear conditioning and induces an autism-like social impairment. Banerjee A , et al. (2016) No -
Rare Variants   (8)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.162+19G>T - intron_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.195G>T p.Met65Ile missense_variant Familial Maternal Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.290C>T p.Ser97Leu missense_variant Familial Maternal Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.425C>T p.Pro142Leu missense_variant Familial Paternal Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.528-11T>G - intron_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.968G>A p.Arg323His missense_variant De novo - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.*197C>T - 3_prime_UTR_variant Familial Paternal Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.634A>G p.Lys212Glu missense_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
4

Minimal Evidence

4

Score Delta: Score remained at 4.4

4

Minimal Evidence

See all Category 4 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as 'acc" in the score cards) could also boost a gene from category 4 to 3.

1/1/2016
icon
4

Increased from to 4

Description

Seven rare variants (minor allele frequency < 1%) in the HOMER1 gene were identified in a cohort of 290 non-syndromic ASD cases; none of these variants were observed in 300 ethnically matched controls. Four of the variants in the HOMER1 gene co-segregated with ASD in multiplex families (Kelleher III et al., 2012). PMID 22267161 demonstrated that altered mGluR5-Homer scaffolds contribute to mGluR5 dysfunction and phenotypes in a fragile X syndrome mouse model. Significant decreases in HOMER1 protein levels were observed in the BA9 and vermis of adult subjects with autism compared to controls in PMID 23803181. Virally-mediated overexpression of Homer1 in the basal and lateral nucleus of the amygdala impaired auditory fear conditioning and reduced social interaction in rats, while having no influence on open-field behavior (Banerjee et al., 2016).

Krishnan Probability Score

Score 0.49045596977077

Ranking 6115/25841 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 0.99592202439131

Ranking 1453/18225 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 0.93595566047827

Ranking 13041/18665 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).
Larsen Cumulative Evidence Score

Score 29

Ranking 74/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Zhang D Score

Score 0.43350097467116

Ranking 1085/20870 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.
CNVs associated with HOMER1(1 CNVs)
5q14.1 15 Deletion-Duplication 27  /  55
Animal Models associated with HOMER1(4 Models)
HOMER1_1_KO_HM 1 Genetic Mus musculus
HOMER1_2_OE_HM 1 Genetic Mus musculus
HOMER1_2_OE_HM_Art 1 Genetic Mus musculus
HOMER1_3_KO_HM 1 Genetic Mus musculus
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
ABI3 ABI family, member 3 Human Protein Binding 51225 Q9P2A4
C19ORF57 chromosome 19 open reading frame 57 Human Protein Binding 79173 Q0VDD7
C1orf116 chromosome 1 open reading frame 116 Human Protein Binding 79098 Q9BW04
C22ORF41 synaptonemal complex central element protein 3 Human Protein Binding 644186 A1L190
KIF2B Kinesin-like protein KIF2B Human Protein Binding 84643 Q8N4N8
Klk1 kallikrein 1 Mouse Protein Binding 16612 P15947
TRPC2 transient receptor potential cation channel, subfamily C, member 2, pseudogene Human Protein Binding 7221 N/A
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