Whole-Exome Sequencing in a South American Cohort Links ALDH1A3, FOXN1 and Retinoic Acid Regulation Pathways to Autism Spectrum Disorders.
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.
Departamento de Ciencias Biológicas, Facultad de Ciencias, Universidad de los Andes, Bogotá D.C., Colombia.
Oscar A
OA
Moreno-Ramos
Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, United States of America.
Ana María
AM
Olivares
Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, United States of America.
Neena B
NB
Haider
Liga Colombiana de Autismo (LICA), Bogotá D.C., Colombia.
Liga Colombiana
LC
de Autismo
Departamento de Ciencias Biológicas, Facultad de Ciencias, Universidad de los Andes, Bogotá D.C., Colombia.
María Claudia
MC
Lattig
D000328:Adult; D000445:Aldehyde Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000067877:Autism Spectrum Disorder / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D001921:Brain / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D002648:Child; D015331:Cohort Studies; D003105:Colombia; D004622:Embryo, Mammalian; D059472:Exome; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010375:Pedigree; D011581:Psychological Tests; D018168:Receptors, Retinoic Acid / Q000235:genetics* / Q000378:metabolism; D020218:Response Elements; D015398:Signal Transduction; D014212:Tretinoin / Q000378:metabolism*
D051858:Forkhead Transcription Factors; D018168:Receptors, Retinoic Acid; C090140:Whn protein; C082925:retinoic acid receptor beta; D014212:Tretinoin; D000445:Aldehyde Oxidoreductases; C018699:aldehyde dehydrogenase (NAD(P)+)