Cloning of a candidate gene (ARG1) from the breakpoint of t(7;20) in an autistic twin pair. R. Sultana1, J. Yu2, W. Raskind3, C. Disteche4, F. de La Barra Monsalvo5, E. Villacres1. 1) Depts of Psychiatry; 2) Molecular Biotechnology; 3) Medicine; 4) Pathology, Univ of Washington, Seattle, WA; 5) Cytogenetics, Univ of Chile, Inta Santiago, Chile.
Autism is a pervasive developmental disorder characterized by markedly impaired social interaction and communication and a restricted repertoire of activity and interests. Evidence from sibling and twin studies supports a genetic basis for this disorder. A genome-wide search for susceptibility loci in autism has identified a region of interest on the long arm of chromosome 7 (International Molecular Genetic Study of Autism Consortium, Hum Mol Genet 7:571-578, 1998). In addition, several structural rearrangements of chromosome 7 have been observed in autistic individuals. These rearrangements include translocations involving 7q11.2 and 7q22 (Gordon et al., 1994; de la Barra et al., 1986) and a paracentric inversion (inv(7)(q22q31.2) (Pericak-Vance et al., 1998). Since structural chromosomal abnormalities can greatly facilitate the localization and cloning of disease causing genes, we studied a concordant autistic twin pair who have translocations involving chromosome band 7q11.2 (t(7;20)(q11.2;p11.2)). Using STS-content mapping and fluorescence in situ hybridization, a BAC contig of 7q11.2 was generated, and two BAC clones spanning the breakpoint of the translocation between chromosomes 7 and 20 present in our autistic twins were identified. Partial sequencing of these BACs and analysis of the available genomic DNA sequence revealed a gene, Autism-Related Gene1 (ARG1), that crosses the chromosome 7q11.2 breakpoint. Partial cDNA sequencing shows that ARG1 is a novel gene and spans a genomic region estimated to be at least 800 kb. Northern analysis showed that the ARG1 transcript is 7.5 kb and is highly expressed in adult and fetal brain. It is also expressed in lung, bladder, ovary, and uterus. The disruption of ARG1 in autistic twins suggests that it is a strong candidate gene for autism.