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

Moreno-Ramos OA, Olivares AM, Haider NB, de Autismo LC, Lattig MC - PLoS ONE (2015)

Bottom Line: 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)).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.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Ciencias Biológicas, Facultad de Ciencias, Universidad de los Andes, 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.

No MeSH data available.


Related in: MedlinePlus

Pedigrees of family FAM07 showing chromatograms where the de novo Novel mutation event occurred for genes ALDH1A3 (c.1618T>C [p.Ile505Thr]) and FOXN1 (c.175C>T [p.Ser49Leu]).
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pone.0135927.g001: Pedigrees of family FAM07 showing chromatograms where the de novo Novel mutation event occurred for genes ALDH1A3 (c.1618T>C [p.Ile505Thr]) and FOXN1 (c.175C>T [p.Ser49Leu]).

Mentions: Two non-synonymous de novo variants were uncovered in the affected child of family Fam07 within ADLH1A3 (RefSeq NM_000693: c.1514T>C (p.I505T)) and FOXN1 (RefSeq NM_003593: c.146C>T (p.S49L)) (Fig 1). SIFT [50] predictions indicate that the FOXN1 alteration is harmful; while PolyPhen [51] and PROVEAN [52] predict that the SNV located in ADLH1A3 is deleterious (Table 2). The other two families: Fam02 and Fam09 did not reveal any de novo mutations on the affected probands. The study further focused on studying both ALDH1A3 and FOXN1 since the variants found have a potential negative impact.


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

Moreno-Ramos OA, Olivares AM, Haider NB, de Autismo LC, Lattig MC - PLoS ONE (2015)

Pedigrees of family FAM07 showing chromatograms where the de novo Novel mutation event occurred for genes ALDH1A3 (c.1618T>C [p.Ile505Thr]) and FOXN1 (c.175C>T [p.Ser49Leu]).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4564166&req=5

pone.0135927.g001: Pedigrees of family FAM07 showing chromatograms where the de novo Novel mutation event occurred for genes ALDH1A3 (c.1618T>C [p.Ile505Thr]) and FOXN1 (c.175C>T [p.Ser49Leu]).
Mentions: Two non-synonymous de novo variants were uncovered in the affected child of family Fam07 within ADLH1A3 (RefSeq NM_000693: c.1514T>C (p.I505T)) and FOXN1 (RefSeq NM_003593: c.146C>T (p.S49L)) (Fig 1). SIFT [50] predictions indicate that the FOXN1 alteration is harmful; while PolyPhen [51] and PROVEAN [52] predict that the SNV located in ADLH1A3 is deleterious (Table 2). The other two families: Fam02 and Fam09 did not reveal any de novo mutations on the affected probands. The study further focused on studying both ALDH1A3 and FOXN1 since the variants found have a potential negative impact.

Bottom Line: 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)).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.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Ciencias Biológicas, Facultad de Ciencias, Universidad de los Andes, 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.

No MeSH data available.


Related in: MedlinePlus