Mutations in autism susceptibility candidate 2 (AUTS2) in patients with mental retardation

Kalscheuer, Vera M.; FitzPatrick, David R.; Tommerup, Niels; Bugge, Merete; Niebuhr, Erik; Neumann, Luitgard M.; Tzschach, Andreas; Shoichet, Sarah A.; Menzel, Corinna; Erdogan, Fikret; Arkesteijn, Ger; Ropers, Hans‐Hilger; Ullmann, Reinhard

doi:10.1007/s00439-006-0284-0

Cited by 117 publications

(109 citation statements)

References 39 publications

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“…30,32,34,38 Our results are consistent with this observation as patients 3 and 4 with duplication of exon 5 have ASDs. Both these duplications are not expected to alter the reading frame, but can result in addition of amino-acid residues to the amino terminus of the protein.…”

Section: Discussionsupporting

confidence: 90%

Detection of copy-number variation in AUTS2 gene by targeted exonic array CGH in patients with developmental delay and autistic spectrum disorders

et al. 2012

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Section: Discussionsupporting

confidence: 90%

Detection of copy-number variation in AUTS2 gene by targeted exonic array CGH in patients with developmental delay and autistic spectrum disorders

et al. 2012

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“…The approach may be particularly suited for phenotypes such as alcohol drinking behavior for which the genetic and environmental determinants may vary over the lifespan (3) and where there may be substantial heterogeneity of both intake and measurement across the very large population samples needed for GWAS. Although the function of AUTS2 is not known, it is developmentally regulated and a highly conserved neuronal nuclear protein (17), first described in the context of autism (13) and mental retardation (18). More recently, it has been associated with Attention Deficit Hyperactivity Disorder (ADHD) (19), which is associated with increased alcohol intake (20).…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene ( AUTS2 ) in the regulation of alcohol consumption

Schumann

Coin

Lourdusamy

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

255

256

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Alcohol consumption is a moderately heritable trait, but the genetic basis in humans is largely unknown, despite its clinical and societal importance. We report a genome-wide association study meta-analysis of ∼2.5 million directly genotyped or imputed SNPs with alcohol consumption (gram per day per kilogram body weight) among 12 population-based samples of European ancestry, comprising 26,316 individuals, with replication genotyping in an additional 21,185 individuals. SNP rs6943555 in autism susceptibility candidate 2 gene ( AUTS2 ) was associated with alcohol consumption at genome-wide significance ( P = 4 × 10 −8 to P = 4 × 10 −9 ). We found a genotype-specific expression of AUTS2 in 96 human prefrontal cortex samples ( P = 0.026) and significant ( P < 0.017) differences in expression of AUTS2 in whole-brain extracts of mice selected for differences in voluntary alcohol consumption. Down-regulation of an AUTS2 homolog caused reduced alcohol sensitivity in Drosophila ( P < 0.001). Our finding of a regulator of alcohol consumption adds knowledge to our understanding of genetic mechanisms influencing alcohol drinking behavior.

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“…(These items were selected because they occurred in at least two unrelated individuals with AUTS2 syndrome.) 1, [3][4][5][6][7][8][9][10][11] frameshift in the full-length AUTS2 transcript, likely to cause haploinsufficiency. Both men have intellectual disability, an autism spectrum disorder, feeding difficulties after birth, mild distal joint contractures and mild dysmorphic features.…”

Section: Discussionmentioning

confidence: 99%

Two male adults with pathogenic AUTS2 variants, including a two-base pair deletion, further delineate the AUTS2 syndrome

Beunders

Munnik

et al. 2014

Eur J Hum Genet

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AUTS2 syndrome is characterized by low birth weight, feeding difficulties, intellectual disability, microcephaly and mild dysmorphic features. All affected individuals thus far were caused by chromosomal rearrangements, variants at the base pair level disrupting AUTS2 have not yet been described. Here we present the full clinical description of two affected men with intragenic AUTS2 variants (one two-base pair deletion in exon 7 and one deletion of exon 6). Both variants are de novo and are predicted to cause a frameshift of the full-length transcript but are unlikely to affect the shorter 3 0 transcript starting in exon 9. The similarities between the phenotypes of both men are striking and further support that AUTS2 syndrome is a single gene disorder. ( European Journal of Human Genetics INTRODUCTIONDisruption of AUTS2 by translocations, inversions or deletions causes a syndromic form of intellectual disability. 1 Forty-four pathogenic disruptions of AUTS2 have been described: 6 translocations and 2 inversions with one breakpoint in AUTS2 and 36 deletions (with a size of 50 kb to 4.5 Mb) containing at least one exon and a maximum of two downstream genes. In most cases parental DNA was available.De novo occurrence could be confirmed in the majority of the patients, but in five families the deletions were inherited from an affected parent (twice), an unaffected father (once) or a parent of whom no clinical data were available (twice). 1-11 A detailed study of 17 affected individuals with a disruption of AUTS2 revealed a distinct AUTS2 syndrome characterized by intellectual disability, microcephaly, mild short stature, feeding problems, hypertonia or hypotonia and facial features, including ptosis, highly arched eyebrows, narrow mouth and micro/retrognathia. 1 The AUTS2 syndrome severity score, expressed as the sum of all features seen more than once in unrelated affected individuals, is a measure of the severity and specificity of the phenotype. The median AUTS2 syndrome severity score of individuals with a genomic rearrangement/ deletion involving the 3 0 region of AUTS2 was significantly higher than that of individuals with 5 0 deletions. The 3 0 end of the gene harbors an alternative transcript that is (like the full-length transcript) expressed in human brain and starts in exon 9. The short transcript is able to rescue the phenotype of AUTS2 zebrafish morphants. These two observations indicate that the 3 0 region of AUTS2 contains important functional domains. 1 Here we report a deletion of two nucleotides, the first pathogenic variant at the base pair level, in a young adult with a syndromic form

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Mutations in autism susceptibility candidate 2 (AUTS2) in patients with mental retardation

Cited by 117 publications

References 39 publications

Detection of copy-number variation in AUTS2 gene by targeted exonic array CGH in patients with developmental delay and autistic spectrum disorders

Detection of copy-number variation in AUTS2 gene by targeted exonic array CGH in patients with developmental delay and autistic spectrum disorders

Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene ( AUTS2 ) in the regulation of alcohol consumption

Two male adults with pathogenic AUTS2 variants, including a two-base pair deletion, further delineate the AUTS2 syndrome

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