Author/Editor     Bacchelli, Elena; Ceroni, Fabiola; Pinto, Dalila; Lomartire, Silvia; Giannandrea, Maila; D'Adamo, Patrizia; Bonora, Elena; Parchi, Piero; Tancredi, Raffaella; Battaglia, Agatino
Title     A CTNNA3 compound heterozygous deletion implicates a role for [alpha]T-catenin in susceptibility to autism spectrum disorder
Type     članek
Vol. and No.     Letnik 6, št. 1
Publication year     2014
ISSN     1866-1955 - Journal of neurodevelopmental disorders
Language     eng
Abstract     Background Autism spectrum disorder (ASD) is a highly heritable, neurodevelopmental condition showing extreme genetic heterogeneity. While it is well established that rare genetic variation, both de novo and inherited, plays an important role in ASD risk, recent studies also support a rare recessive contribution. Methods We identified a compound heterozygous deletion intersecting the CTNNA3 gene, encoding [alpha]T-catenin, in a proband with ASD and moderate intellectual disability. The deletion breakpoints were mapped at base-pair resolution, and segregation analysis was performed. We compared the frequency of CTNNA3 exonic deletions in 2,147 ASD cases from the Autism Genome Project (AGP) study versus the frequency in 6,639 controls. Western blot analysis was performed to get a quantitative characterisation of Ctnna3 expression during early brain development in mouse. Results The CTNNA3 compound heterozygous deletion includes a coding exon, leading to a putative frameshift and premature stop codon. Segregation analysis in the family showed that the unaffected sister is heterozygote for the deletion, having only inherited the paternal deletion. While the frequency of CTNNA3 exonic deletions is not significantly different between ASD cases and controls, no homozygous or compound heterozygous exonic deletions were found in a sample of over 6,000 controls. Expression analysis of Ctnna3 in the mouse cortex and hippocampus (P0-P90) provided support for its role in the early stage of brain development. Conclusion The finding of a rare compound heterozygous CTNNA3 exonic deletion segregating with ASD, the absence of CTNNA3 homozygous exonic deletions in controls and the high expression of Ctnna3 in both brain areas analysed implicate CTNNA3 in ASD susceptibility.
Keywords     autism spectrum disorder
CTNNA3
cell adhesion
motnje avtističnega spektra
CTNNA3
celične adhezije