Somatic NKX2-5 mutations as a novel mechanism of disease in complex congenital heart disease

Reamon-Buettner, Stella Marie; Borlak, Jürgen

doi:10.1136/jmg.2003.017483

Cited by 90 publications

(90 citation statements)

References 20 publications

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“…Somatic mutations can not be detected by genetic analysis of lymphocytic DNA alone, and mosaicism may reduce the likelihood of detection in the affected tissue. Therefore, mutations in cardiac tissues may be absent or sporadic in blood lymphocytes of the same person (40). In the present study, 2 novel heterozygous mutations of GATA6 (p.G367X and p.G394C) were identified in the malformed heart tissues of 2 out of 52 patients with TOF.…”

Section: Discussionmentioning

confidence: 81%

“…Somatic mutations have been identified Somatic mutations in the GATA6 gene underlie sporadic tetralogy of Fallot in GATA4 and its molecular partners, NKX2-5 and TBX5, as well as the transcription factor HAND1 and HEY2 in cardiac tissue derived from hearts with CHD (40)(41)(42)(43)(44)(45)(46)(47)(48). GATA6 is another member of the GATA family, and its expression and function overlap at least partially with those of GATA4, NKX2-5 and TBX5 during cardiovascular genesis, which makes it logical to hypothesize that somatic GATA6 mutations are involved in the pathogenesis of TOF.…”

Section: Introductionmentioning

confidence: 99%

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Somatic mutations in the GATA6 gene underlie sporadic tetralogy of Fallot

Huang

Xue

et al. 2012

International Journal of Molecular Medicine

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Abstract. Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease associated with significant morbidity and mortality in humans. However, the molecular etiology underlying TOF in most patients remains largely unknown. In the present study, sequence analysis of the GATA6 gene was performed from fresh-frozen cardiac tissues and matched blood samples of 52 unrelated patients who underwent surgical repair of TOF. The cardiac tissues and matched blood specimens from 46 patients who underwent cardiac valve replacement due to rheumatic heart disease and blood samples from 200 healthy individuals as controls were genotyped. The functional characteristics of the mutations were assessed using a luciferase reporter assay system. Based on the results, two novel heterozygous GATA6 mutations, p.G367X and p.G394C, were identified in the cardiac tissues of 2 TOF patients, respectively. No mutations were found in the cardiac tissues from 46 patients with rheumatic heart disease and in the blood samples from the 298 participants. Functional analysis demonstrated that the GATA6 mutants were consistently associated with significantly reduced transcriptional activation compared with their wildtype counterpart. This is the first report on the link of somatic GATA6 mutation to TOF, providing novel insight into the molecular mechanism involved in TOF.

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Section: Discussionmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Somatic mutations in the GATA6 gene underlie sporadic tetralogy of Fallot

Huang

Xue

et al. 2012

International Journal of Molecular Medicine

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“…Similar to these findings, the figure of 3/53 mutations (approximately 6%) in our patient cohort with positive family history suggests that the NKX2-5 mutations could be a major cause of familial CHD. Notably, the remarkable genetic heterogeneity of CHD was proven by an inability to detect mutations in nearly 99% of our cohort patients, despite somatic NKX2-5 mutations being a likely mechanism of CHD in some patients (Reamon-Buettner and Borlak, 2004). Hence, the contribution of genes other than NKX2-5 to CHD pathogenesis seems probable.…”

Section: Discussionmentioning

confidence: 99%

Novel NKX2-5 mutations responsible for congenital heart disease

Wang

Xy²,

Yq³

2011

Genet. Mol. Res.

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ABSTRACT. Congenital heart disease (CHD) is the most common birth defect and is the leading cause of infant morbidity and mortality resulting from birth defects. Increasing evidence demonstrates that genetic variation in the NKX2-5 gene, which encodes a homeobox-containing transcription factor crucial to cardiogenesis, is an important molecular determinant for CHD. Nevertheless, the genetic components underlying CHD remain largely unknown. We screened NKX2-5 for potential molecular defects in patients with CHD. The entire coding region of NKX2-5 was initially sequenced in a cohort of 268 unrelated patients with CHD. The relatives of the patients carrying identified mutations and 200 unrelated control individuals were subsequently genotyped. Three novel heterozygous missense NKX2-5 mutations, p.Q22K, p.R36S, and p.E54K, were identified in three families with autosomal dominantly inherited atrial septal defect, ventricular septal defect, and tetralogy of Fallot, respectively. These mutations, absent in 200 control individuals, appear to be highly conserved evolutionarily and co-segregated with CHD in the families, with complete penetrance. These findings expand the spectrum of mutations in NKX2-5 associated with CHD and provide new insight into the molecular etiology involved in the pathogenesis of CHD, which signifies potential implications for genetic diagnosis and gene-specific therapy for this common disease in newborns.

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“…More importantly, many studies have demonstrated that somatic mutations play crucial role in congenital heart diseases (56,57). Reamon-Buettner et al (56) have found somatic NKX2-5 sequence variants by direct sequencing in >95% of human hearts (n=68) with septal defects.…”

Section: Discussionmentioning

confidence: 99%

Sequence variations of NKX2-5 and HAND1 genes in patients with atrial isomerism

Hatemi¹,

Güleç²,

Çine³

et al. 2011

Anadolu Kardiyol Derg

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ÖZETAmaç: Atriyal izomerizm, kalp gibi normalde asimetrik olan organlardaki lateralizasyon defektleriyle karakterize olan doğumsal bir anomalidir. Atriyal izomerizmin, erken gelişim sırasındaki moleküler defektler nedeniyle oluştuğu düşünülmektedir. NKX2-5, kardiyogenezi başlatan ve kardiyogenezin sonraki transkripsiyonel olaylarını düzenleyen kalbe özgü bir transkripsiyon faktörüdür. HAND1 ise kalpte ekspres olan, asimetrik ekspresyon paterni ile karakterize başka bir transkripsiyon faktörüdür. Çalışmamızda, NKX2-5 ve HAND1 genlerindeki mutasyonların atriyal izomerizm etiyolojisinde rol oynayıp oynamadığını anlamak için, atriyal izomerizm hastalarında bu iki geni incelemeyi amaçladık. Yöntemler: Bu vaka-kontrol çalışması atriyal izomerizm tanısı alan veya atriyal izomerizm nedeniyle cerrahi tedavi gören 70 hasta ve HAND1 için 80, NKX2-5 için, 40 sağlıklı kontrolden oluşturulmuştur. NKX2-5 ve HAND1 genlerinin tüm ekzonları ve ekzon-intron sınırları SSCP ile analiz edilmiş, şüpheli örnekler mutasyon analizi için dizilenmiştir. Bilinen polimorfizmler ve mutasyonlar için uygun restriksiyon enzimi ile enzim kesimi uygulanmıştır. Hasta ve kontrol grupları arasındaki allel ve genotip sıklıklarını Ki-kare ve Fisher testleri kullanılarak karşılaştırıldı. Bulgular: Kontrol ve hastalarda, HAND1 geninin intronik bölgesinde bir C>G dönüşümü tanımladık. Mutant allelin hasta grubundaki sıklığı (%11.42) kontrol grubundakinden (%2.5) daha yüksek bulundu (p=0.046). Mutant allel taşıyan genotipler ile atriyal izomerizm arasındaki bağlantı sınırda anlamlı bulundu (p=0.054). NKX2-5 geninde, bir hastada heterozigot durumda Q170X (Gln170ter) mutasyonu tanımladık. Tanımlanan dizi farklılıkları ile hastaların klinik özellikleri arasında herhangi bir ilişki bulunmadı. Sonuç: Sonuçlarımız, HAND1 veya NKX2-5 genlerindeki mutasyon veya dizi farklılıklarının, atriyal izomerizm etiyolojisi veya patogenezinde rol oynayabileceğini akla getirmektedir. (Anadolu Kardiyol Derg 2011; 11: 319-28) Anahtar kelimeler: İzomerizm, NKX2-5, HAND1, mutasyon ABSTRACT Objective: Atrial isomerism is a congenital disorder, which is characterized by lateralization defects in normally asymmetrical developing organs like the heart. Atrial isomerism is supposed to be caused by molecular defects during early development. The NKX2-5 is a cardiac specific transcription factor, which initiates and regulates downstream transcriptional cascades of cardiogenesis. The HAND1 is another transcription factor expressed in the heart, and it is characterized by an asymmetrical pattern of expression. In this study, we aimed to test whether mutations in NKX2-5 and HAND1 genes play a role in the etiology of atrial isomerism. Methods: This case-control study consisted of 70 patients who underwent surgical treatment for congenital heart defects including atrial isomerism, 80 healthy subjects (HAND1 gene) and 40 healthy subjects (NKX2-5 gene). All exons and exon-intron boundaries of NKX2-5 and HAND1 genes were analyzed by SSCP, and suspected samples were sequenced for mutation analysi...

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Somatic NKX2-5 mutations as a novel mechanism of disease in complex congenital heart disease

Cited by 90 publications

References 20 publications

Somatic mutations in the GATA6 gene underlie sporadic tetralogy of Fallot

Somatic mutations in the GATA6 gene underlie sporadic tetralogy of Fallot

Novel NKX2-5 mutations responsible for congenital heart disease

Sequence variations of NKX2-5 and HAND1 genes in patients with atrial isomerism

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