6533b838fe1ef96bd12a51cf
RESEARCH PRODUCT
Disruption of the ASTN2 / TRIM32 locus at 9q33.1 is a risk factor in males for Autism Spectrum Disorders, ADHD and other neurodevelopmental phenotypes
Patricia I. BaderChristina ChryslerPietro CavalliMohammed UddinCarlo PoggianiNoam SoreniAndrew D. PatersonRoberto CicconeDiana PostorivoSebastiano A. MusumeciLonnie ZwaigenbaumEli HatchwellMichael E. TalkowskiSarah M. NikkelSarah M. NikkelPaul D. ArnoldH. Melanie BedfordVincenzo AntonaSylvia LamoureuxCaroline Mackie OgilvieTimothy WilksJohn WeiEva M TomiakUgo CavallariMarc Woodbury-smithOrsetta ZuffardiSusan WalkerBob ArgiropoulosBob ArgiropoulosBob ArgiropoulosJudy ChernosJudy ChernosJudy ChernosCharu DeshpandeJeffrey R. MacdonaldBai-lin WuBai-lin WuBai-lin WuThomas NalpathamkalamLone W. LaulundAnna Maria NardoneGioacchino ScaranoBridget A. FernandezChristian R. MarshallJohn TrounceSusan LeatherPeter SzatmariAnath C. LionelJennelle C. HodgeAnn C WhiteDimitri J. StavropoulosMatteo Della MonicaDavid S CobbCassandra K. RunkeZhuozhi WangCorrado RomanoMichael T. GeraghtyMichael T. GeraghtyLeopoldo ZelanteJoo Wook AhnMatthew J. GazzelloneLeonardo ZoccanteMarsha SpeevakBhooma ThiruvahindrapuramRussell SchacharJennifer L. HoweJill Clayton-smithChristina FagerbergR. Brian LowryFrancesca NovaraMarco FicheraJill A. RosenfeldCharlotte Brasch-andersenStephen W. SchererGiovanna PellecchiaDivya MandyamVamsee PillalamarriYu AnWendy RobertsAbdul NoorDaniel TolsonMelissa T. CarterPeggy S. EisJoyce SoJennifer CrosbieMassimo CarellaRyan K. C. YuenAndrea K. VaagsMark J SorensenDaniele MericoKristiina TammimiesKristiina TammimiesYiping ShenYiping ShenYiping Shensubject
MaleReceptors Cell Surface/geneticsAutismChild Development Disorders Pervasive/geneticsGene ExpressionGenome-wide association studyMedical and Health SciencesTripartite Motif ProteinsRisk FactorsReceptors2.1 Biological and endogenous factorsProtein IsoformsNerve Tissue Proteins/geneticsCopy-number variationAetiologyChildGenetics (clinical)Sequence DeletionPediatricGenetics & HeredityGeneticseducation.field_of_studySingle NucleotideArticlesGeneral MedicineExonsBiological SciencesMental HealthPhenotypeAutism spectrum disorderOrgan SpecificityCerebellar cortexChild PreschoolCell SurfaceSpeech delayFemalemedicine.symptomTranscription Initiation SiteAttention Deficit Disorder with Hyperactivity/geneticsChromosomes Human Pair 9HumanPair 9AdultPediatric Research InitiativeChild Development DisordersAdolescentDNA Copy Number VariationsIntellectual and Developmental Disabilities (IDD)Ubiquitin-Protein LigasesPopulationTranscription Factors/geneticsNerve Tissue ProteinsReceptors Cell SurfaceBiologyPolymorphism Single NucleotideChromosomesYoung AdultClinical ResearchProtein Isoforms/geneticsBehavioral and Social ScienceGeneticsmedicineAttention deficit hyperactivity disorderHumansGenetic Predisposition to DiseasePolymorphismPreschooleducationMolecular BiologyGenetic Association StudiesPervasiveGlycoproteinsHuman GenomeNeurosciencesInfant NewbornGlycoproteins/geneticsInfantNewbornmedicine.diseaseBrain DisordersAttention Deficit Disorder with HyperactivityChild Development Disorders PervasiveCase-Control StudiesAutismTranscription Factorsdescription
Rare copy number variants (CNVs) disrupting ASTN2 or both ASTN2 and TRIM32 have been reported at 9q33.1 by genome-wide studies in a few individuals with neurodevelopmental disorders (NDDs). The vertebrate-specific astrotactins, ASTN2 and its paralog ASTN1, have key roles in glial-guided neuronal migration during brain development. To determine the prevalence of astrotactin mutations and delineate their associated phenotypic spectrum, we screened ASTN2/TRIM32 and ASTN1 (1q25.2) for exonic CNVs in clinical microarray data from 89 985 individuals across 10 sites, including 64 114 NDD subjects. In this clinical dataset, we identified 46 deletions and 12 duplications affecting ASTN2. Deletions of ASTN1 were much rarer. Deletions near the 3' terminus of ASTN2, which would disrupt all transcript isoforms (a subset of these deletions also included TRIM32), were significantly enriched in the NDD subjects (P = 0.002) compared with 44 085 population-based controls. Frequent phenotypes observed in individuals with such deletions include autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), speech delay, anxiety and obsessive compulsive disorder (OCD). The 3'-terminal ASTN2 deletions were significantly enriched compared with controls in males with NDDs, but not in females. Upon quantifying ASTN2 human brain RNA, we observed shorter isoforms expressed from an alternative transcription start site of recent evolutionary origin near the 3' end. Spatiotemporal expression profiling in the human brain revealed consistently high ASTN1 expression while ASTN2 expression peaked in the early embryonic neocortex and postnatal cerebellar cortex. Our findings shed new light on the role of the astrotactins in psychopathology and their interplay in human neurodevelopment.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2014-05-15 |