AUTS2 (autism susceptibility candidate 2)

2013-10-01   Jean-Loup Huret 

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

Identity

HGNC
LOCATION
7q11.22
LOCUSID
ALIAS
FBRSL2,MRD26
FUSION GENES

DNA/RNA

Description

The gene spans 1.19 Mb. 19 coding exons.

Transcription

There are 16 transcripts (splice variants). Six transcripts contains an open reading frame.

Proteins

Atlas Image
AUTS2 protein and domains.

Description

1259 amino acids (aa); from N-term to C-term, AUTS2 contains: nuclear localization sequences (aa: 11-27; 70-79; 120-141); Pro-rich regions (aa: 288-471; 544-646); a Dwarfin consensus sequence (aa: 325-453); a Ser-rich region (aa: 383-410); a PY motif (aa: 515-519); a hexanucleotide repeat (aa: 524-540; (cagcac/cagcac/cagcac/cagcac/acc/cac/cagcac/cagcac/cagcac) at nucleotide 1901-1949 (exon 9)); His-rich regions (aa: 525-548, 1122-1181); a Fibrosin homology region (aa: 645-798); a topoisomerase homology region (aa: 880-920); a trinucleotide repeat (aa: 1126-1133 (cac)8, at nucleotide 3701-3732 (exon 19)), and also N-glycosylation sites (aa 395-398, 785-788, 955-958, 1009-1012), cAMP and cGMP- dependent protein kinase phosphorylation sites (aa: 13-16, 77-80, 116-119, 832-835, 849-852, 975-978, 1235-1238), SH3 interaction domains (P67, P72, P73, P266, P332, P361, P364, P467, P468, P471, P638, P806, P1234), and a SH2 interaction domain (Y971) (Sultana et al., 2002; Bedogni et al., 2010b; Oksenberg and Ahituv, 2013).

Expression

AUTS2 is primarily expressed in the central nervous system, and also in skeletal muscle and kidney, and with lower expression in other tissues (placenta, lung, and leukocytes) (Sultana et al., 2002). AUTS2 is highly expressed in the embryo, and in more restricted areas in the adult (Oksenberg and Ahituv, 2013).
Auts2 in the mouse embryo is expressed in the cortical preplate, in frontal cortex, hippocampus and cerebellum, including Purkinje cells and deep nuclei, in developing dorsal thalamus, olfactory bulb, inferior colliculus and substantia nigra (Bedogni et al., 2010a).

Localisation

AUTS2 is a nuclear protein.

Function

TBR1, a postmitotic projection-neuron specific transcription factor, binds the AUTS2 promoter and activates AUTS2 in developing neocortex in vivo (Bedogni et al., 2010b; Srinivasan et al., 2012). Suppression of auts2 in zebrafish embryos caused microcephaly, and a reduction in developing midbrain neurons and also in sensory and motor neurons (Beunders et al., 2013; Oksenberg et al., 2013). ZMAT3 (a target gene of TP53) downregulation produced significant reductions in AUTS2 mRNA levels (Sedaghat et al., 2012).
Enhancers that were mutated in patients with dyslexia or with autism spectrum disorder were described; AUTS2 has been found as a rapidly evolving gene in homo sapiens sapiens, compared to Neanderthals, and non-human primates. It is suggested that AUTS2 has an important role in the evolution of human cognitive traits (Oksenberg et al., 2013).

Implicated in

Entity name
t(7;9)(q11;p13) PAX5/AUTS2
Note
PAX5 is involved in B-cell differentiation. Entry of common lymphoid progenitors into the B cell lineage depends on E2A, EBF1, and PAX5. Genes repressed by PAX5 expression in early B cells are restored in their function in mature B cells and plasma cells, and PAX5 repressed (Medvedovic et al., 2011).
Disease
Pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL).
Prognosis
Three cases to date, two boys and one girl, aged 0.6, 2.8, and 3.1 years (Kawamata 2008; Coyaud et al., 2010; Denk et al., 2012). Two patients presented with a high WBC, and also had a central nervous system involvement at a time during course of the disease. Patients were assigned to different risk arms of the respective clinical trials, as noted by Denk et al., 2012. The three patients achieved complete remission (CR), but two (those with high risk features) relapsed and died at 1.7 and 3.4 years after diagnosis, indicating a rather poor outcome (Denk et al., 2012). Only one patient is still in CR and well 2.2 years after diagnosis.
Cytogenetics
The t(7;9)(q11;p13) was the sole abnormality in one case. Unbalanced translocation in two cases, due to the loss of the der(7)t(7;9).
Hybrid gene
5 PAX5-3 AUTS2. Fusion of PAX5 exon 6 to AUTS2 exon 4 or 6.
Fusion protein
1289 or 1311 amino acids depending on whether exon 6 or 4 of AUTS2 is fused to PAX5. The predicted fusion protein contains the paired domain, the octapeptide, and the homeodomain of PAX5 and the proline rich, the Dwarfin consensus sequence, the serine rich, the PY motif, the hexanucleotide repeat, the histidine rich, the fibrosin homology region, the topoisomerase homology region, and the trinucleotide repeat of AUTS2.
Atlas Image
Fusion protein PAX5/AUTS2.
Entity name
Other cancers
Disease
Loss of heterozygocity was found in an adenocarcinoma of the lung, but more data is needed (Weir et al., 2007). Copy number variation was found in a single case of mixed germ cell tumor containing yolk sac tumor and teratoma (Stadler et al., 2012).
Entity name
Syndromic phenotype, mental retardation, neurodevelopmental and psychiatric disorders, including autism spectrum disorder
Note
A review in Oksenberg and Ahituv, 2013 shows a map of the gene with the structural variants and abnormalities in relation to the various phenotypes described.
Disease
Syndromic phenotype: A study on 24 patients with deletions of part of AUTS2 allowed the identification of a variable syndromic phenotype including intellectual disability, autism, short stature, microcephaly, cerebral palsy, and facial dysmorphisms. The authors delineated an "AUTS2 syndrome severity score" of the phenotypic diversity, that correlated with genotypic data: individuals with deletions in the 5 part of the gene showed a milder phenotype than those with a deletion in the 3 part of the gene (Beunders et al., 2013).
Mental retardation: A patient with developmental delay had an intragenic deletion within AUTS2 (Jolley et al., 2013). Three unrelated mentally disabled patients were found to carry a balanced translocation that truncates AUTS2. Patients were borderline or severely mentally retarded and carried different deletions in AUTS2 (Kalscheuer et al., 2007). AUTS2 has been found disrupted in balanced chromosomal abnormality in patients with abnormal neurodevelopment (Huang et al., 2010; Talkowski et al., 2012).
Autism spectrum disorder (ASD): Small copy-number variations (CNVs) that disrupt AUTS2 (duplications or deletions of exons) were found in two patients with developmental delay, and two with autism spectrum disorder (Nagamani et al., 2013). AUTS2 has been found disrupted in a monozygotic twin pair concordant for autism (Sultana et al., 2002). Duplication in the AUTS2 gene was identified in a family with ASD (Ben-David et al., 2011).
Pathological behaviour: A variant in AUTS2 was associated with excessive alcohol consumption (Edenberg and Foroud, 2013; Kapoor et al., 2013). AUTS2 variants (rs6943 allele A) are correlated with heroin dependence, and reduced AUTS2 gene expression might confer increased susceptibility (Chen et al., 2013). rs6943555 A allele was also found associated with alcohol consumption (Schumann et al., 2011), and with suicide committed after drinking (Chojnicka et al., 2013). Amino acids sequence variant in AUTS2 were found in a large family with high risk for suicide, but also with a significant co-morbidity for affective disorders, alcohol disorders, psychotic disorders, and drug abuse disorders (Coon et al., 2013).
Epilepsy: AUTS2 deletions were identified in one patient with juvenile myoclonic epilepsy and in another patient with an unclassified non-lesional epilepsy with features of atypical benign partial epilepsy (Mefford et al., 2010).

Bibliography

Pubmed IDLast YearTitleAuthors
206159562010Tbr1 regulates regional and laminar identity of postmitotic neurons in developing neocortex.Bedogni F et al
216805582011Identification of a functional rare variant in autism using genome-wide screen for monoallelic expression.Ben-David E et al
233329182013Exonic deletions in AUTS2 cause a syndromic form of intellectual disability and suggest a critical role for the C terminus.Beunders G et al
229957652013Genetic analysis of AUTS2 as a susceptibility gene of heroin dependence.Chen YH et al
234373402013Possible association between suicide committed under influence of ethanol and a variant in the AUTS2 gene.Chojnicka I et al
242529052013Genetic risk factors in two Utah pedigrees at high risk for suicide.Coon H et al
207239772010PAX5-AUTS2 fusion resulting from t(7;9)(q11.2;p13.2) can now be classified as recurrent in B cell acute lymphoblastic leukemia.Coyaud E et al
225787762012PAX5-AUTS2: a recurrent fusion gene in childhood B-cell precursor acute lymphoblastic leukemia.Denk D et al
237123132013Genetics and alcoholism.Edenberg HJ et al
206353382010A de novo balanced translocation breakpoint truncating the autism susceptibility candidate 2 (AUTS2) gene in a patient with autism.Huang XL et al
236501832013De novo intragenic deletion of the autism susceptibility candidate 2 (AUTS2) gene in a patient with developmental delay: a case report and literature review.Jolley A et al
172116392007Mutations in autism susceptibility candidate 2 (AUTS2) in patients with mental retardation.Kalscheuer VM et al
237436752013A meta-analysis of two genome-wide association studies to identify novel loci for maximum number of alcoholic drinks.Kapoor M et al
186979402008Cloning of genes involved in chromosomal translocations by high-resolution single nucleotide polymorphism genomic microarray.Kawamata N et al
219709552011Pax5: a master regulator of B cell development and leukemogenesis.Medvedovic J et al
205026792010Genome-wide copy number variation in epilepsy: novel susceptibility loci in idiopathic generalized and focal epilepsies.Mefford HC et al
228721022013Detection of copy-number variation in AUTS2 gene by targeted exonic array CGH in patients with developmental delay and autistic spectrum disorders.Nagamani SC et al
233496412013Function and regulation of AUTS2, a gene implicated in autism and human evolution.Oksenberg N et al
214714582011Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption.Schumann G et al
223473642012Genomic analysis of wig-1 pathways.Sedaghat Y et al
231442232012A network of genetic repression and derepression specifies projection fates in the developing neocortex.Srinivasan K et al
228631922012Rare de novo germline copy-number variation in testicular cancer.Stadler ZK et al
121607232002Identification of a novel gene on chromosome 7q11.2 interrupted by a translocation breakpoint in a pair of autistic twins.Sultana R et al
225213612012Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries.Talkowski ME et al
179824422007Characterizing the cancer genome in lung adenocarcinoma.Weir BA et al

Other Information

Locus ID:

NCBI: 26053
MIM: 607270
HGNC: 14262
Ensembl: ENSG00000158321

Variants:

dbSNP: 26053
ClinVar: 26053
TCGA: ENSG00000158321
COSMIC: AUTS2

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000158321ENST00000342771Q8WXX7
ENSG00000158321ENST00000403018Q8WXX7
ENSG00000158321ENST00000406775Q8WXX7
ENSG00000158321ENST00000439256H7C2P0
ENSG00000158321ENST00000443672H7C090
ENSG00000158321ENST00000449547H7C1G5
ENSG00000158321ENST00000611706Q75MD7
ENSG00000158321ENST00000615871A0A087WVB5
ENSG00000158321ENST00000643587A0A2R8YEX6
ENSG00000158321ENST00000643936A0A2R8Y516
ENSG00000158321ENST00000644359A0A2R8Y568
ENSG00000158321ENST00000644506A0A024RDL5
ENSG00000158321ENST00000644939A0A2R8Y8C6
ENSG00000158321ENST00000644949A0A2R8Y6Q9
ENSG00000158321ENST00000647140A0A2R8Y522
ENSG00000158321ENST00000656200A0A590UJP3
ENSG00000158321ENST00000656998A0A590UKA2
ENSG00000158321ENST00000659051A0A590UJA2
ENSG00000158321ENST00000664521A0A590UK55

Expression (GTEx)

0
5
10
15
20
25
30

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
195468592010Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes.189
214714582011Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption.123
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
255191322014An AUTS2-Polycomb complex activates gene expression in the CNS.77
192400612009Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-kappaB signalling.75
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
248593392014Brain-expressed exons under purifying selection are enriched for de novo mutations in autism spectrum disorder.62
233329182013Exonic deletions in AUTS2 cause a syndromic form of intellectual disability and suggest a critical role for the C terminus.53
233496412013Function and regulation of AUTS2, a gene implicated in autism and human evolution.42
195678912009Genetic utility of broadly defined bipolar schizoaffective disorder as a diagnostic concept.38

Citation

Jean-Loup Huret

AUTS2 (autism susceptibility candidate 2)

Atlas Genet Cytogenet Oncol Haematol. 2013-10-01

Online version: http://atlasgeneticsoncology.org/gene/51794/auts2-(autism-susceptibility-candidate-2)