Identification and characterization of the TRIP8 and REEP3 genes on chromosome 10q21.3 as novel candidate genes for autism

Abstract

Autism is a genetic neurodevelopmental disorder of unknown cause and pathogenesis. The identification of genes involved in autism is expected to increase our understanding of its pathogenesis. Infrequently, neurodevelopmental disorders like autism are associated with chromosomal anomalies. To identify candidate genes for autism, we initiated a positional cloning strategy starting from individuals with idiopathic autism carrying a de novo chromosomal anomaly. We report on the clinical, cytogenetic and molecular findings in a male person with autism, no physical abnormalities and normal IQ, carrying a de novo balanced paracentric inversion 46,XY,inv(10)(q11.1;q21.3). The distal breakpoint disrupts the TRIP8 gene, which codes for a protein predicted to be a transcriptional regulator associated with nuclear thyroid hormone receptors. However, no link between thyroid gland and autism has been reported so far. In addition, the same breakpoint abolishes expression of a nearby gene, REEP3, through a position effect. Receptor Expression-Enhancing Proteins (REEP) 3 is one of the six human homologs of yeast Yop1p, a probable regulator of cellular vesicle trafficking between the endoplasmatic reticulum and the Golgi network. These observations suggest that TRIP8 and REEP3 are both positional candidate genes for autism. In addition, our data indicate that in the selection of positional candidate genes when studying chromosomal aberrations, position effects should be taken into account.

Position effect leading to haploinsufficiency in a mosaic ring chromosome 14 in a boy with autism

“…6 aCGH and real-time quantitative PCR (RTQ-PCR) analyses were performed as described. 3,7 Specific primers used for RTQ-PCR are listed as supplementary data.…”

“…Isolation of mRNA and gDNA (RNeasy and DNeasy Mini kits, Invitrogen), reverse transcription of mRNA to cDNA (DNaseI treatment and Superscript III, Invitrogen), and gDNA/cDNA SNP analysis by subsequent PCR amplification and sequencing were performed as described. 3 Specific primers used for amplification and sequencing of the regions of interest are listed as supplementary data.…”

“…Moreover, so called position effects, where the expression of genes located at a distance from the imbalance are affected, may further complicate the interpretation. 2,3 One area where chromosomal aberrations have been instrumental in the identification of candidate genes and chromosomal regions is autism. Visible cytogenetic abnormalities are detected in 45% of affected children, involving many different loci on all chromosomes.…”

Two patients with balanced translocations and autistic disorder: CSMD3 as a candidate gene for autism found in their common 8q23 breakpoint area

“…17 An alternative and potentially successful approach aimed at eliciting candidate genes or candidate regions is the detailed analysis of the boundaries of the cytogenetic abnormalities found in individuals with autism. 18 Recent studies estimated a rate 45% of cytogenetic abnormalities (including unbalanced translocations, inversions, rings and interstitial deletions and duplications) in ASDs, and a high number of such cases have been described in the literature with regard to most chromosomes. 5,19,20 Two studies 6,9 greatly strengthen the growing awareness that a substantial fraction of ASDs is caused by genomic rearrangements.…”

Selection on Inversion Breakpoints Favors Proximity to Pairing Sensitive Sites in Drosophila melanogaster

“…Alternatively, they may result from selective processes if breakpoints in certain genomic regions are selectively favorable. Hence, at present it is not clear if inversion breakpoint positions constitute an important source of natural selection affecting the evolution of chromosomal inversions (although see Tadin-Strapps et al 2004;Castermans et al 2007;and Corbett-Detig and Hartl 2012 for examples of negative selection on inversion breakpoint effects).…”