Alternative titles; symbols
HGNC Approved Gene Symbol: AUTS2
Cytogenetic location: 7q11.22 Genomic coordinates (GRCh38) : 7:69,598,475-70,793,506 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q11.22 | Intellectual developmental disorder, autosomal dominant 26 | 615834 | Autosomal dominant | 3 |
By sequencing clones obtained from a size-fractionated brain cDNA library, Ishikawa et al. (1997) cloned KIAA0442. The deduced 1,172-amino acid protein shares sequence homology with rat atrophin-1-related protein (RERE; 605226). RT-PCR detected KIAA0442 in all tissues examined, with highest expression in kidney, followed by ovary, prostate, and small intestine.
Sultana et al. (2002) studied a monozygotic twin pair concordant for autism (see 209850) and for an identical balanced t(7;20)(q11.2;p11.2) translocation. They identified and characterized a novel gene, which they designated 'AUTS2,' that spans the 7q11.2 breakpoint. The gene is identical to the KIAA0442 gene identified by Ishikawa et al. (1997). The predicted 1,259-amino acid protein contains 2 proline-rich domains and regions that share homology with the dwarfin family consensus sequence and with topoisomerase (see 126420). It has a PY motif, several putative phosphorylation sites and N-myristoylation sites, and 2 putative N-glycosylation sites. The KIAA0442 protein shares 93% amino acid identity with its murine homolog. Northern blot analysis detected strong expression of 7.5- and 8.0-kb transcripts in fetal and adult brain. KIAA0442 was also strongly expressed in skeletal muscle and kidney, with lower levels in placenta, lung, and leukocytes. In fetal brain, KIAA0442 was expressed in frontal, parietal, and temporal lobes, but not in the occipital lobe. Sultana et al. (2002) identified several smaller splice variants of KIAA0442.
Beunders et al. (2013) identified a short 3-prime AUTS2 mRNA variant starting in the middle of exon 9. The reading frame of the short transcript is identical to that of the full-length AUTS2 transcript and is predicted to encode a polypeptide of 697 amino acids instead of the 1,259 amino acids of the full-length protein.
Gao et al. (2014) investigated the role of AUTS2 as part of an AUTS2-containing Polycomb repressive complex (PRC1-AUTS2) and in the context of neurodevelopment. In contrast to the canonical role of PRC1 in gene repression, PRC1-AUTS2 activates transcription. Biochemical studies demonstrated that the casein kinase-2 (CK2; see 115440) component of PRC1-AUTS2 neutralizes PRC1 repressive activity, whereas AUTS2-mediated recruitment of p300 (602700) leads to gene activation. Chromatin immunoprecipitation followed by sequencing demonstrated that AUTS2 regulates neuronal gene expression through promoter association. Conditional targeting of Auts2 in the mouse central nervous system (CNS) leads to various developmental defects. Gao et al. (2014) concluded that their findings revealed a natural means of subverting PRC1 activity, linking key epigenetic modulators with neuronal functions and diseases.
By genomic sequence analysis, Sultana et al. (2002) determined that the KIAA0442 gene spans 1.2 Mb and contains 19 exons.
By radiation hybrid analysis, Ishikawa et al. (1997) mapped the KIAA0442 gene to chromosome 7. By FISH, Sultana et al. (2002) mapped the AUTS2 gene to chromosome 7q11.2.
Intragenic Copy Number Variation in MRD26
By combining the results of diagnostic testing of 49,684 individuals, Beunders et al. (2013) identified 24 microdeletions that affected at least 1 exon of AUTS2, as well as 1 translocation and 1 inversion each with a breakpoint within the AUTS2 locus. The authors then analyzed 16,784 controls from 12 cohorts by using arrays with high-density coverage of the AUTS2 locus. Although 9 deletions were found, none of them disrupted an AUTS2 exon. The difference between exonic deletions in the cases (24 of 49,651) and those in controls (0 of 16,784) was highly significant (p = 0.00092), suggesting that exonic disruptions of AUTS2 give rise to a highly penetrant phenotype in humans. Of the 24 probands with an exonic AUTS2 deletion, 10 individuals carried an intragenic deletion (MRD26; 615834); 4 of these resulted in frameshift while the other 6 were in-frame. Dysmorphic features were more pronounced in persons with 3-prime AUTS2 deletions. This part of the gene encodes a C-terminal isoform (with an alternative transcription start site) expressed in the human brain. Consistent with their genetic data, Beunders et al. (2013) found that suppression of auts2 in zebrafish embryos caused microcephaly that could be rescued by either the full-length or the C-terminal isoform of AUTS2.
Nagamani et al. (2013) reported 4 patients with copy number variations (CNVs) ranging in size from 133 to 319 kb that disrupted AUTS2. Two patients were sibs who inherited an identical 179-kb duplication of exon 5 from their mother. The other 2 patients had different intragenic deletions that involved exons 6 through 14. All patients had developmental delay. Both of the patients with the duplication had autism spectrum disorder. One had microcephaly, while the other was normocephalic; the normocephalic patient had seizures. The mother of these patients had microcephaly and mild intellectual disability. One deletion patient had macrocephaly, dysmorphic facial features, failure to thrive, scoliosis, and atrial septal defect; brain MRI was normal. Her 133-kb deletion arose de novo. The second deletion patient had a head circumference in the 11th percentile at 3 years of age. She had no features of autism or seizures, and brain MRI was normal. Her deletion, which was 319 kb, encompassed that of the other patient.
In 2 unrelated men with MRD26, Beunders et al. (2015) identified 2 de novo heterozygous small deletions in the AUTS2 gene (607270.0003 and 607270.0004). Functional studies of the variants were not performed, but both were predicted to result in haploinsufficiency. The deletions were found by exome sequencing or array analysis.
Association with Impaired Intellectual Development
Sultana et al. (2002) studied a monozygotic twin pair concordant for severe mental retardation with autistic features and epilepsy who both had an identical balanced t(7;20)(q11.2;p11.2) translocation that interrupted the KIAA0442 gene. Sultana et al. (2002) sought to determine whether genetic variation in the KIAA0442 gene contributed to idiopathic autism (see, e.g., 209850). DNA sequence analysis of autism subjects and controls revealed 22 biallelic polymorphic sites. For all sites, both alleles were observed in both cases and controls. Thus, no autism-specific mutation was observed. Association analysis with 2 exonic polymorphic sites and linkage analysis of 4 dinucleotide repeat markers, 2 within and 2 flanking KIAA0442, were negative. The findings suggested that KIAA0442 is unlikely to be an autism susceptibility gene for idiopathic autism.
Kalscheuer et al. (2007) reported 3 unrelated mentally disabled patients, 2 boys and a girl, all of whom had a de novo balanced translocation of 7q11.2 that interrupted the KIAA0442 gene. One boy had severe profound mental retardation with seizures, bilateral optic nerve hypoplasia, thin corpus callosum, hypoplastic brainstem, and sensorineural hearing loss. Dysmorphic features included macroglossia, micrognathia, low-set ears, distal arthrogryposis of the hands, clubfeet, hypospadias, kyphoscoliosis, vesicoureteral reflux, and gastroesophageal reflux. The other boy was moderately affected with speech delay, short attention span, and cataracts at age 17 years. The girl had borderline mental retardation, hyperactivity, sleep disturbances, and mild exophthalmia. Genetic analysis identified disruption of the KIAA0442 gene in all 3, although a contribution of the second breakpoint could not be excluded. The translocations were t(3;7)(p21.3;q11.2), t(7;11)(q11.2;p11.2), and t(7;13)(q11.2;q22), respectively. Autistic features were not observed.
Huang et al. (2010) reported a 4.5-year-old boy with delayed psychomotor development and mild to moderate autism associated with a de novo balanced translocation, t(6;7)(q14;q11.2). The 7q11.2 breakpoint occurred within intron 1 of the AUTS2 gene, and the 6q14 breakpoint occurred in a region of no known genes, although the HTR1B gene (182131) was nearby. The boy had deficits in relating to people, emotional response, listening and visual response, and nonverbal communication. He also had mild dysmorphic features, such as epicanthal folds, prominent low-set ears, broad nasal bridge, deep philtrum, and micrognathia.
Green et al. (2010) published a draft sequence of the Neandertal genome. Comparisons of the Neandertal genome to the genomes of 5 present-day humans from different parts of the world identified a number of genomic regions that may have been affected by positive selection in ancestral modern humans, including genes involved in metabolism and in cognitive and skeletal development. Green et al. (2010) identified a total of 212 regions containing putative selective sweeps. The region with the strongest statistical signal contained a stretch of 293 consecutive SNP positions in the first half of the gene AUTS2, where only ancestral alleles were observed in the Neandertals. Mutations in several genes in regions of selective sweeps, including DYRK1A (600855), NRG3 (605533), and CADPS2 (609978) have been associated with disorders affecting cognitive capacities. Green et al. (2010) hypothesized that multiple genes involved in cognitive development were positively selected during the early history of modern humans. Green et al. (2010) also showed that Neandertals shared more genetic variants with present-day humans in Eurasia than with present-day humans in sub-Saharan Africa, suggesting that gene flow from Neandertals into the ancestors of non-Africans occurred before the divergence of Eurasian groups from each other.
Gao et al. (2014) assessed AUTS2 function in the brain by using Auts2 conditional knockout mice, which were generated by Cre-lox technology. Although AUTS2 disruptions normally occur on 1 of the 2 alleles in humans, Gao et al. (2014) characterized full homozygous knockout as well as heterozygous knockout of Auts2 to better understand the effects of Auts2 disruption. In humans, approximately 80% of all AUTS2 disruptions are associated with either low birth weight or small stature. Consistent with this observation, Gao et al. (2014) observed both a striking visual and quantitative reduction in the size of the Auts2 knockout relative to wildtype littermates, with heterozygotes showing an intermediate phenotype across early development. Developmental delay typically encompasses impairments in reaching normal sensorimotor, cognition, and communication (for example, speech) milestones, characteristics of the AUTS2 phenotype. Auts2 knockout mice were deficient in both righting reflex and ultrasonic vocalizations emitted, as well as in negative geotaxis.
In a 2-year-old girl (patient 4) with developmental delay and dysmorphic features (MRD26; 615834), Beunders et al. (2013) identified an in-frame deletion encompassing exons 3 and 4 of the AUTS2 gene, resulting in the deletion of 46 amino acids. The deletion was maternally inherited. The patient had microcephaly, proptosis, short palpebral fissures, narrow mouth, and patent foramen ovale/atrial septal defect. The patient's mother had learning difficulties, cleft lip, ptosis, and retrognathia.
In a 32-year-old woman (patient 9) with impaired intellectual development and dysmorphic features (MRD26; 615834), Beunders et al. (2013) identified an in-frame deletion of exons 6 through 9 of the AUTS2 gene. The patient's father did not carry the deletion; the mother was unavailable for testing. The patient had short stature and microcephaly. Feeding difficulties had been reported, and autistic behavior was present. Dysmorphic features included hypertelorism, highly arched eyebrows, proptosis, short and upslanting palpebral fissures, ptosis, strabismus, prominent nasal tip with anteverted nares, short upturned philtrum, and narrow mouth. Kyphosis/scoliosis and arthrogryposis/shallow palmar creases were also present. This patient was the most severely affected among those reported by Beunders et al. (2013).
In a 24-year-old man with autosomal dominant intellectual developmental disorder-26 (MRD26; 615834), Beunders et al. (2015) identified a de novo heterozygous 2-bp deletion (c.857_858delAA, NM_015570.2) in exon 7 of the AUTS2 gene, resulting in a frameshift and premature termination (Lys286fs). The mutation was found by exome sequencing and confirmed by Sanger sequencing. Functional studies were not performed, but the variant was predicted to result in haploinsufficiency of the longest AUTS2 transcript. Exome sequencing also identified a de novo heterozygous P408L substitution at a highly conserved residue in the ABI2 gene (606442). Missense mutations in the ABI2 gene are not known to be pathogenic, but an additional effect of the variant on the phenotype could not be excluded.
In a 20-year-old man with autosomal dominant intellectual developmental disorder-26 (MRD26; 615834), Beunders et al. (2015) identified a de novo heterozygous small intragenic deletion (chr7.(69,985,843_69,991,859)_(70,221,259_70,228,020)del, GRCh37) encompassing exon 6 of the AUTS2 gene. The deletion was found by array analysis. The deletion was predicted to cause a frameshift of the full-length transcript without affecting the shorter 3-prime transcript, consistent with haploinsufficiency. Functional studies were not performed.
Beunders, G., de Munnik, S. A., Van der Aa, N., Ceulemans, B., Voorhoeve, E., Groffen, A. J., Nillesen, W. M., Meijers-Heijboer, E. J., Kooy, R. F., Yntema, H. G., Sistermans, E. A. Two male adults with pathogenic AUTS2 variants, including a two-base pair deletion, further delineate the AUTS2 syndrome. Europ. J. Hum. Genet. 23: 803-807, 2015. [PubMed: 25205402] [Full Text: https://doi.org/10.1038/ejhg.2014.173]
Beunders, G., Voorhoeve, E., Golzio, C., Pardo, L. M., Rosenfeld, J. A., Talkowski, M. E., Simonic, I., Lionel, A. C., Vergult, S., Pyatt, R. E., van de Kamp, J., Nieuwint, A., and 51 others. Exonic deletions in AUTS2 cause a syndromic form of intellectual disability and suggest a critical role for the C terminus. Am. J. Hum. Genet. 92: 210-220, 2013. [PubMed: 23332918] [Full Text: https://doi.org/10.1016/j.ajhg.2012.12.011]
Gao, Z., Lee, P., Stafford, J. M., von Schimmelmann, M., Schaefer, A., Reinberg, D. An AUTS2-Polycomb complex activates gene expression in the CNS. Nature 516: 349-354, 2014. [PubMed: 25519132] [Full Text: https://doi.org/10.1038/nature13921]
Green, R. E., Krause, J., Briggs, A. W., Maricic, T., Stenzel, U., Kircher, M., Patterson, N., Li, H., Zhai, W., Fritz, M. H.-Y., Hansen, N. F., Durand, E. Y., and 44 others. A draft sequence of the Neandertal genome. Science 328: 710-722, 2010. [PubMed: 20448178] [Full Text: https://doi.org/10.1126/science.1188021]
Huang, X.-L., Zou, Y. S., Maher, T. A., Newton, S., Milunsky, J. M. A de novo balanced translocation breakpoint truncating the autism susceptibility candidate 2 [AUTS2] gene in a patient with autism. (Letter) Am. J. Med. Genet. 152A: 2112-2114, 2010. [PubMed: 20635338] [Full Text: https://doi.org/10.1002/ajmg.a.33497]
Ishikawa, K., Nagase, T., Nakajima, D., Seki, N., Ohira, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. VIII. 78 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 4: 307-313, 1997. [PubMed: 9455477] [Full Text: https://doi.org/10.1093/dnares/4.5.307]
Kalscheuer, V. M., FitzPatrick, D., Tommerup, N., Bugge, M., Niebuhr, E., Neumann, L. M., Tzschach, A., Shoichet, S. A., Menzel, C., Erdogan, F., Arkesteijn, G., Ropers, H.-H., Ullmann, R. Mutations in autism susceptibility candidate 2 (AUTS2) in patients with mental retardation. Hum. Genet. 121: 501-509, 2007. [PubMed: 17211639] [Full Text: https://doi.org/10.1007/s00439-006-0284-0]
Nagamani, S. C. S., Erez, A., Ben-Zeev, B., Frydman, M., Winter, S., Zeller, R., El-Khechen, D., Escobar, L., Stankiewicz, P., Patel, A., Cheung, S. W. Detection of copy-number variation in AUTS2 gene by targeted exonic array CGH in patients with developmental delay and autistic spectrum disorders. Europ. J. Hum. Genet. 21: 343-346, 2013. [PubMed: 22872102] [Full Text: https://doi.org/10.1038/ejhg.2012.157]
Sultana, R., Yu, C.-E., Yu, J., Munson, J., Chen, D., Hua, W., Estes, A., Cortes, F., de la Barra, F., Yu, D., Haider, S. T., Trask, B. J., Green, E. D., Raskind, W. H., Disteche, C. M., Wijsman, E., Dawson, G., Storm, D. R., Schellenberg, G. D., Villacres, E. C. Identification of a novel gene on chromosome 7q11.2 interrupted by a translocation breakpoint in a pair of autistic twins. Genomics 80: 129-134, 2002. [PubMed: 12160723] [Full Text: https://doi.org/10.1006/geno.2002.6810]