Whole-Exome Sequencing in a South American Cohort Links ALDH1A3, FOXN1 and Retinoic Acid Regulation Pathways to Autism Spectrum Disorders

• Published in: PloS one Vol. 10; no. 9; p. e0135927
• Main Authors: Moreno-Ramos, Oscar A, Olivares, Ana María, Haider, Neena B, de Autismo, Liga Colombiana, Lattig, María Claudia
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 09.09.2015; Public Library of Science (PLoS)
• Subjects: Acids; Adult; Aldehyde Oxidoreductases - genetics; Aldehyde Oxidoreductases - metabolism; Animals; Autism; Autism Spectrum Disorder - genetics; Autism Spectrum Disorder - metabolism; Autism Spectrum Disorder - pathology; Base Sequence; Brain; Brain - growth & development; Brain - metabolism; Brain - pathology; Brain research; Child; Chromatin; Cohort Studies; Colombia; Cortex (piriform); Demographic aspects; Disorders; DNA sequencing; Embryo, Mammalian; Embryos; Enzymes; Etiology; Exome; Female; Fetuses; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Gene expression; Gene Expression Regulation, Developmental; Genes; Genetic aspects; Genetic variation; Genomes; High-Throughput Nucleotide Sequencing; Humans; Immunoprecipitation; Male; Mental development; Methods; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Mouse devices; Mutation; Pedigree; Pervasive developmental disorders; Physiological aspects; Piriform cortex; Proteins; Psychological Tests; Receptors, Retinoic Acid - genetics; Receptors, Retinoic Acid - metabolism; Regulatory sequences; Response Elements; Retinoic acid; Risk factors; Rodents; Signal Transduction; Tretinoin - metabolism; Colombia
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0135927

Autism spectrum disorders (ASDs) are a range of complex neurodevelopmental conditions principally characterized by dysfunctions linked to mental development. Previous studies have shown that there are more than 1000 genes likely involved in ASD, expressed mainly in brain and highly interconnected among them. We applied whole exome sequencing in Colombian-South American trios. Two missense novel SNVs were found in the same child: ALDH1A3 (RefSeq NM_000693: c.1514T>C (p.I505T)) and FOXN1 (RefSeq NM_003593: c.146C>T (p.S49L)). Gene expression studies reveal that Aldh1a3 and Foxn1 are expressed in ~E13.5 mouse embryonic brain, as well as in adult piriform cortex (PC; ~P30). Conserved Retinoic Acid Response Elements (RAREs) upstream of human ALDH1A3 and FOXN1 and in mouse Aldh1a3 and Foxn1 genes were revealed using bioinformatic approximation. Chromatin immunoprecipitation (ChIP) assay using Retinoid Acid Receptor B (Rarb) as the immunoprecipitation target suggests RA regulation of Aldh1a3 and Foxn1 in mice. Our results frame a possible link of RA regulation in brain to ASD etiology, and a feasible non-additive effect of two apparently unrelated variants in ALDH1A3 and FOXN1 recognizing that every result given by next generation sequencing should be cautiously analyzed, as it might be an incidental finding.