Annexins: A Putative Role in the Etiology of ASD

Thursday, May 17, 2012
Sheraton Hall (Sheraton Centre Toronto)
9:00 AM
I. C. Conceição1, C. Correia2,3, I. Sousa2, A. F. Sequeira4, B. Oliveira5, J. Coelho5, J. Almeida6, C. Café7, F. Duque7, D. Pinto8, W. Roberts9,10, K. Gao11, J. K. Lowe12,13, S. W. Scherer14, D. H. Geschwind13,15,16, G. Oliveira7 and A. M. Vicente2,3, (1)Instituto Nacional de Saúde Dr Ricardo Jorge, Lisboa, Portugal, (2)Instituto Gulbenkian de Ciência, Oeiras, Portugal, (3)Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisboa, Portugal, (4)Instituto Gulbenkian de Ciência, Lisbon, Portugal, (5)Instituto Nacional de Saúde Dra Ricardo Joge, Lisbon, Portugal, (6)Unidade de Neurodesenvolvimento e Autismo – Centro de Desenvolvimento Luís Borges (CDLB), Hospital Pediátrico Carmona da Mota (HP) – Centro Hospitalar e Universitário de Coimbra (CHUC), Coimbra, Portugal, (7)Hospital Pediátrico de Coimbra, Coimbra, Portugal, (8)The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada, (9)Holland Bloorview Kids Rehabilitation Hospital, Toronto, ON, Canada, (10)Autism Research Unit, The Hospital for Sick Children, Toronto, ON, Canada, (11)David Geffen School of Medicine, University of California, Los Angeles, CA, (12)Neurology, University of California, Los Angeles, Los Angeles, CA, (13)Center for Neurobehavioral Genetics, University of California, Los Angeles, Los Angeles, CA, (14)101 College St, 14-701, University of Toronto, Toronto, ON, Canada, (15)University of California at Los Angeles, Los Angeles, CA, (16)Center for Neurobehavioral Genetics, University of California, Los Angeles, CA
Background: Autism Spectrum Disorders (ASD) have a strong genetic component, with an estimated heritability of over 90%. Recent studies carried out by the Autism Genome Project (AGP) consortium suggest that rare Copy Number Variants (CNV), characterized by submicroscopic chromosomal deletions and duplications, are more frequent in ASD compared to controls, and may play an important role in susceptibility to this disorder.

Objectives: Establishing the relevance of rare potentially pathogenic CNVs for autism susceptibility identified by the AGP whole genome CNV analysis is the major goal of our study.

Methods: We have been characterizing potentially pathogenic rare CNVs identified by the AGP whole genome CNV analysis of 1771 ASD individuals using the Illumina Infinium1M SNP microarray. CNV validation in patients and relatives and characterization of the breakpoints was performed by qPCR and Long-range PCR. Expression analysis was done by RT-PCR. Sanger and 454 Roche sequencing were performed for identification of additional rare variants.

Results: We have identified CNVs in two Annexin genes, namely ANXA1 and ANXA7. A small in tandem inherited duplication overlapping ANXA1 gene at 9q21.13 was identified in 12 patients from 9 families. This duplication involving the 4 last exons of the gene is not present in 8000 European control individuals. The breakpoints were the same for all individuals carrying the duplication, which is probably mediated by a sequence of microhomology of 3 nucleotides identified. In the 3 patients analyzed, there was no change in ANXA1 expression levels. Coding or splicing variants were not identified in any of the 479 additional individuals screened for the 13 exons of the gene, but three new variants in the 3’UTR were identified in three patients, one of them in a putative miRNA binding site. Additionally, one autistic patient showed a rare de novo deletion located at 10q22, and encompassing 14 genes, including ANXA7, together with ZMYND17, PPP3CB and CAMK2G, which is absent in 4964 controls of European ancestry with no psychiatric disease history. Accurate breakpoint determination showed that it is smaller than predicted by CNV identification algorithms, including only part of CAMK2G, and that a 39 nucleotide addition occurred with the deletion, a mutational mechanism known to occur in this type of chromosomal rearrangement. Expression analysis of ANXA7, ZMYND17 and PPP3CB in this patient, in comparison with controls, is ongoing.

Conclusions: Annexin 1 plays an important role in anti-inflammatory response and neuroprotection, and is likely to be an effect on the mTOR pathway (mammalian Target Of Rapamycin), a major regulator of cellular growth in mitotic cells, in which several mutations have been described in autistic individuals. Previous studies identified a genetic association of the ANXA7, PPP3CB and ZMYND17 region with schizophrenia, and significant expression alterations in schizophrenic patients. ANXA7 encodes Annexin7, involved in membrane fusion. PPP3CB plays an important role in synaptic plasticity, learning and memory. ZMYND17 has no known function.  Our results suggest that alterations in these genes may be risk factors co-observed in autism and schizophrenia. Additional genetic and functional studies may lead to a better understanding of the common pathways between these neuropsychiatric disorders.

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