Mutations in the 3-untranslated region of GATA4 as molecular hotspots for congenital heart disease CHDReportar como inadecuado

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BMC Medical Genetics

, 8:38

First Online: 25 June 2007Received: 16 November 2006Accepted: 25 June 2007


BackgroundThe 3-untranslated region 3-UTR of mRNA contains regulatory elements that are essential for the appropriate expression of many genes. These regulatory elements are involved in the control of nuclear transport, polyadenylation status, subcellular targetting as well as rates of translation and degradation of mRNA. Indeed, 3-UTR mutations have been associated with disease, but frequently this region is not analyzed. To gain insights into congenital heart disease CHD, we have been analyzing cardiac-specific transcription factor genes, including GATA4, which encodes a zinc finger transcription factor. Germline mutations in the coding region of GATA4 have been associated with septation defects of the human heart, but mutations are rather rare. Previously, we identified 19 somatically-derived zinc finger mutations in diseased tissues of malformed hearts. We now continued our search in the 609 bp 3-UTR region of GATA4 to explore further molecular avenues leading to CHD.

MethodsBy direct sequencing, we analyzed the 3-UTR of GATA4 in DNA isolated from 68 formalin-fixed explanted hearts with complex cardiac malformations encompassing ventricular, atrial, and atrioventricular septal defects. We also analyzed blood samples of 12 patients with CHD and 100 unrelated healthy individuals.

ResultsWe identified germline and somatic mutations in the 3-UTR of GATA4. In the malformed hearts, we found nine frequently occurring sequence alterations and six dbSNPs in the 3-UTR region of GATA4. Seven of these mutations are predicted to affect RNA folding. We also found further five nonsynonymous mutations in exons 6 and 7 of GATA4. Except for the dbSNPs, analysis of tissue distal to the septation defect failed to detect sequence variations in the same donor, thus suggesting somatic origin and mosaicism of mutations. In a family, we observed c.+119A > T in the 3-UTR associated with ASD type II.

ConclusionOur results suggest that somatic GATA4 mutations in the 3-UTR may provide an additional molecular rationale for CHD.

AbbreviationsCHDCongenital heart disease

ASDAtrial septal defect

VSDVentricular septal defect

AVSDAtrioventricular septal defect

UTRUntranslated region

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2350-8-38 contains supplementary material, which is available to authorized users.

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Autor: Stella Marie Reamon-Buettner - Si-Hyen Cho - Juergen Borlak


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