Human Gene Module / Chromosome X / AP1S2

AP1S2adaptor related protein complex 1 sigma 2 subunit

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
3 / 7
Rare Variants / Common Variants
11 / 0
Aliases
AP1S2, DC22,  MGC:1902,  MRX59,  MRXS21,  MRXSF,  SIGMA1B
Associated Syndromes
-
Chromosome Band
Xp22.2
Associated Disorders
EP, ASD, EPS
Relevance to Autism

A maternally-inherited nonsense variant in the AP1S2 gene (c.154C>T; p.Arg52Ter) was identified in three affected males from a XLMR pedigree: two siblings with profound mental retardation (MR) and DSM-IV diagnoses of ASD, and a maternal uncle with profound MR (Borck et al., 2008).

Molecular Function

Adaptor protein complex 1 is found at the cytoplasmic face of coated vesicles located at the Golgi complex, where it mediates both the recruitment of clathrin to the membrane and the recognition of sorting signals within the cytosolic tails of transmembrane receptors. This complex is a heterotetramer composed of two large, one medium, and one small adaptin subunit. The protein encoded by this gene serves as the small subunit of this complex and is a member of the adaptin protein family.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
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SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to AP1S2 (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Mutations in the gene encoding the Sigma 2 subunit of the adaptor protein 1 complex, AP1S2, cause X-linked mental retardation Tarpey PS , et al. (2006) No -
2 Support Mutations in the AP1S2 gene encoding the sigma 2 subunit of the adaptor protein 1 complex are associated with syndromic X-linked mental retardation with hydrocephalus and calcifications in basal ganglia Saillour Y , et al. (2007) No -
3 Primary Clinical, cellular, and neuropathological consequences of AP1S2 mutations: further delineation of a recognizable X-linked mental retardation syndrome Borck G , et al. (2008) No ASD
4 Recent Recommendation AP1S2 is mutated in X-linked Dandy-Walker malformation with intellectual disability, basal ganglia disease and seizures (Pettigrew syndrome) Cacciagli P , et al. (2013) No Epilepsy/seizures
5 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
6 Support - Hiraide T et al. (2021) Yes -
7 Support - Hu C et al. (2022) Yes -
Rare Variants   (11)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.4C>T p.Gln2Ter stop_gained Familial Maternal - 35741772 Hu C et al. (2022)
c.25C>T p.Arg9Cys missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.289-1G>C - splice_site_variant Familial Maternal Simplex 18428203 Borck G , et al. (2008)
c.179+1G>A - splice_site_variant Familial Maternal Unknown 33644862 Hiraide T et al. (2021)
c.154C>T p.Arg52Ter stop_gained Familial Maternal Multi-generational 18428203 Borck G , et al. (2008)
c.106C>T p.Gln36Ter stop_gained Familial Maternal Multi-generational 17186471 Tarpey PS , et al. (2006)
c.154C>T p.Arg52Ter stop_gained Familial Maternal Multi-generational 17186471 Tarpey PS , et al. (2006)
c.180-5del - splice_site_variant Familial Maternal Multi-generational 17186471 Tarpey PS , et al. (2006)
c.226G>T p.Glu76Ter stop_gained Familial Maternal Multi-generational 17617514 Saillour Y , et al. (2007)
c.288+5G>A - splice_site_variant Familial Maternal Multi-generational 17617514 Saillour Y , et al. (2007)
c.426+1G>T - splice_site_variant Familial Maternal Multi-generational 23756445 Cacciagli P , et al. (2013)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

Defects in AP1S2 are the cause of mental retardation X-linked type 59 (MRX59) [MIM:300630] (Tarpey et al., 2006; Saillour et al., 2007; Borck et al., 2008). More recently, a splice-site variant in AP1S2 was found to segregate with disease in a four-generation family with MRXS5, also known as Pettigrew syndrome [OMIM:304340] (Cacciagli et al., 2013). A maternally-inherited nonsense variant in the AP1S2 gene (c.154C>T; p.Arg52Ter) was identified in Borck et al., 2008 in three affected males from a XLID pedigree: two siblings with profound intellectual disability and DSM-IV diagnoses of ASD, and a maternal uncle with profound intellectual disability. A de novo missense variant in this gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014; this variant was not reported in dbSNP or ESP, and it was reported by PolyPhen-2 to be possibly damaging (Mis2) in Sanders et al, 2015.

Score Delta: Score remained at S

criteria met
See SFARI Gene'scoring criteria
S

Syndromic

See all Category S Genes

The 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."

1/1/2021
S
icon
S

Score remained at S

Description

Defects in AP1S2 are the cause of mental retardation X-linked type 59 (MRX59) [MIM:300630] (Tarpey et al., 2006; Saillour et al., 2007; Borck et al., 2008). More recently, a splice-site variant in AP1S2 was found to segregate with disease in a four-generation family with MRXS5, also known as Pettigrew syndrome [OMIM:304340] (Cacciagli et al., 2013). A maternally-inherited nonsense variant in the AP1S2 gene (c.154C>T; p.Arg52Ter) was identified in Borck et al., 2008 in three affected males from a XLID pedigree: two siblings with profound intellectual disability and DSM-IV diagnoses of ASD, and a maternal uncle with profound intellectual disability. A de novo missense variant in this gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014; this variant was not reported in dbSNP or ESP, and it was reported by PolyPhen-2 to be possibly damaging (Mis2) in Sanders et al, 2015.

Reports Added
[Genetic and phenotypic analysis of 101 patients with developmental delay or intellectual disability using whole-exome sequencing2021]
10/1/2019
S
icon
S

Score remained at S

New Scoring Scheme
Description

Defects in AP1S2 are the cause of mental retardation X-linked type 59 (MRX59) [MIM:300630] (Tarpey et al., 2006; Saillour et al., 2007; Borck et al., 2008). More recently, a splice-site variant in AP1S2 was found to segregate with disease in a four-generation family with MRXS5, also known as Pettigrew syndrome [OMIM:304340] (Cacciagli et al., 2013). A maternally-inherited nonsense variant in the AP1S2 gene (c.154C>T; p.Arg52Ter) was identified in Borck et al., 2008 in three affected males from a XLID pedigree: two siblings with profound intellectual disability and DSM-IV diagnoses of ASD, and a maternal uncle with profound intellectual disability. A de novo missense variant in this gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014; this variant was not reported in dbSNP or ESP, and it was reported by PolyPhen-2 to be possibly damaging (Mis2) in Sanders et al, 2015.

Reports Added
[New Scoring Scheme]
Krishnan Probability Score

Score 0.49484395562086

Ranking 3388/25841 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.
Original Source
ExAC Score

Score 0.79261116950346

Ranking 3984/18225 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
Original Source
Sanders TADA Score

Score 0.89776143446917

Ranking 6166/18665 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).
Original Source
Larsen Cumulative Evidence Score

Score 4

Ranking 300/461 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.
Original Source
Zhang D Score

Score 0.021944692916626

Ranking 8031/20870 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.
Original Source
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