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

Oscar A Moreno-Ramos; Ana María Olivares; Neena B Haider; Liga Colombiana de Autismo; María Claudia Lattig

doi:10.1371/journal.pone.0135927

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

PLoS One. 2015 Sep 9;10(9):e0135927. doi: 10.1371/journal.pone.0135927. eCollection 2015.

Authors

Oscar A Moreno-Ramos¹, Ana María Olivares², Neena B Haider², Liga Colombiana de Autismo³, María Claudia Lattig¹

Affiliations

¹ Departamento de Ciencias Biológicas, Facultad de Ciencias, Universidad de los Andes, Bogotá D.C., Colombia.
² Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, United States of America.
³ Liga Colombiana de Autismo (LICA), Bogotá D.C., Colombia.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aldehyde Oxidoreductases / genetics*
Aldehyde Oxidoreductases / metabolism
Animals
Autism Spectrum Disorder / genetics*
Autism Spectrum Disorder / metabolism
Autism Spectrum Disorder / pathology
Base Sequence
Brain / growth & development
Brain / metabolism
Brain / pathology
Child
Cohort Studies
Colombia
Embryo, Mammalian
Exome*
Female
Forkhead Transcription Factors / genetics*
Forkhead Transcription Factors / metabolism
Gene Expression Regulation, Developmental
High-Throughput Nucleotide Sequencing
Humans
Male
Mice
Mice, Inbred C57BL
Molecular Sequence Data
Pedigree
Psychological Tests
Receptors, Retinoic Acid / genetics*
Receptors, Retinoic Acid / metabolism
Response Elements
Signal Transduction
Tretinoin / metabolism*

Substances

Forkhead Transcription Factors
Receptors, Retinoic Acid
Whn protein
retinoic acid receptor beta
Tretinoin
Aldehyde Oxidoreductases
aldehyde dehydrogenase (NAD(P)+)

Grants and funding

Support for sequencing was provided by proyecto semilla 2013-1, Facultad de ciencias, Universidad de los Andes (OAM) and Vicerrectoria de investigaciones, Universidad de los Andes (MCL). Support for molecular and animal studies was provided by the Chase Fund (NBH) and Edward N. & Della L. Thome Memorial Foundation, Bank Of America, N.A., Trustee (NBH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.