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Regulatory variationin a TBX5 enhancerleads to isolatedcongenital heartdisease Scott SmemoLuciene Cristina GastalhoCamposIvan P. Moskowitz2012 год

Regulatory variation in a TBX5 enhancer leads to isolated congenital heart disease
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Аннотация: Recent studies have identified the genetic underpinnings of a growing number of diseases through targeted exome sequencing. However, this strategy ignores the large component of the genome that does not code for proteins, but is nonetheless biologically functional. To address the possible involvement of regulatory variation in congenital heart diseases (CHDs), we searched for regulatory mutations impacting the activity of TBX5, a dosage-dependent transcription factor with well-defined roles in the heart and limb development that has been associated with the Holt-Oram syndrome (heart-hand syndrome), a condition that affects 1/100 000 newborns. Using a combination of genomics, bioinformatics and mouse genetic engineering, we scanned ∼700 kb of the TBX5 locus in search of cis-regulatory elements. We uncovered three enhancers that collectively recapitulate the endogenous expression pattern of TBX5 in the developing heart. We re-sequenced these enhancer elements in a cohort of non-syndromic patients with isolated atrial and/or ventricular septal defects, the predominant cardiac defects of the Holt-Oram syndrome, and identified a patient with a homozygous mutation in an enhancer ∼90 kb downstream of TBX5. Notably, we demonstrate that this single-base-pair mutation abrogates the ability of the enhancer to drive expression within the heart in vivo using both mouse and zebrafish transgenic models. Given the population-wide frequency of this variant, we estimate that 1/100 000 individuals would be homozygous for this variant, highlighting that a significant number of CHD associated with TBX5 dysfunction might arise from non-coding mutations in TBX5 heart enhancers, effectively decoupling the heart and hand phenotypes of the Holt-Oram syndrome.
Год издания: 2012
Авторы: Scott Smemo, Luciene Cristina Gastalho Campos, Ivan P. Moskowitz, José Eduardo Krieger, Alexandre C. Pereira, Marcelo A. Nóbrega
Издательство: Oxford University Press
Источник: Human Molecular Genetics
Ключевые слова: Congenital heart defects research, Congenital Heart Disease Studies, Genomic variations and chromosomal abnormalities
Другие ссылки: Human Molecular Genetics (PDF)
Human Molecular Genetics (HTML)
Europe PMC (PubMed Central) (PDF)
Europe PMC (PubMed Central) (HTML)
PubMed Central (HTML)
PubMed (HTML)