NKX2.5 mutations in patients with non-syndromic congenital heart disease

Gioli-Pereira, Luciana; Pereira, Alexandre C.; Mesquita, Sonia M. F.; Xavier‐Neto, José; Lopes, Antônio Augusto; Krieger, José Eduardo

doi:10.1016/j.ijcard.2008.08.035

Cited by 56 publications

(36 citation statements)

References 21 publications

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“…Nonsyndromic Ebstein anomaly can occur as a sporadic or a familial defect [Lo et al, 1979;Pi erard et al, 1985;McIntosh et al, 1992;Uyan et al, 2002]. Mutational screening for the genes involved in the cardiac morphogenesis have disclosed mutations in NKX2.5 [Woodrow Benson et al, 1999;Baekvad-Hansen et al, 2006;Zhang et al, 2006;Gioli-Pereira et al, 2010] and MYH7 genes [Budde et al, 2007] in a few individuals.…”

Section: Introductionmentioning

confidence: 99%

Ebstein anomaly: Genetic heterogeneity and association with microdeletions 1p36 and 8p23.1

Digilio

Bernardini

Lepri

et al. 2011

American J of Med Genetics Pt A

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Ebstein anomaly is an uncommon congenital heart defect (CHD), characterized by downward displacement of the tricuspid valve into the right ventricle. To uncover the genetic associations with Ebstein anomaly, we have searched chromosomal imbalances using standard cytogenetic and array-CGH analysis, and single gene conditions associated with syndromic Ebstein anomaly (with extracardiac anomalies), and screened GATA4 and NKX2.5 mutations in nonsyndromic patients (without extracardiac anomalies). Between January 1997 and September 2009, 44 consecutive patients with Ebstein anomaly were evaluated in two centers of Pediatric Cardiology. Ebstein anomaly was syndromic in 12 (27%) patients, and nonsyndromic in 32 (73%). A recognizable syndrome or complex was diagnosed by clinical criteria in seven patients. In one syndromic patient an 18q deletion was diagnosed by standard cytogenetic analysis. Array-CGH analysis performed in 10 of the 12 syndromic patients detected an interstitial deletion of about 4 Mb at 8p23.1 in one patient, and a deletion 1pter > 1p36.32/dup Xpter- > Xp22.32 in another patient. In the 28 of 32 nonsyndromic patients who underwent molecular testing, no mutation in GATA4 and NKX2.5 genes were detected. We conclude that Ebstein anomaly is a genetically heterogeneous defect, and that deletion 1p36 and deletion 8p23.1 are the most frequent chromosomal imbalances associated with Ebstein anomaly. Candidate genes include the GATA4 gene (in patients with del 8p23.1), NKX2.5 (based on published patients with isolated Ebstein anomaly) and a hypothetical gene in patients with del 1p36).

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Section: Introductionmentioning

confidence: 99%

Ebstein anomaly: Genetic heterogeneity and association with microdeletions 1p36 and 8p23.1

Digilio

Bernardini

Lepri

et al. 2011

American J of Med Genetics Pt A

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“…Although NKX2-5 gene was not studied in patients with atrial isomerism to date, several mutations in this gene have been detected in many other heart diseases like TOF (25), non-syndromic congenital heart diseases (26,51,52), atrial septal defects (27,48) and recently patent foramen ovale (53). All these studies suggest that mutations of NKX2-5 gene seem like to be responsible for various congenital heart diseases.…”

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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“…The first genetic etiology for ASD was the discovery that mutations in the transcrip- tion factor, TBX5, are a reason of septation defects in the Holt-Oram syndrome, which is characterized by cardiac and upper limb malformations [13]. Mutations in the cardiac transcription factor, Nkx2-5, were recognized in families who primarily showed non-syndromic ASD and atrioventricular conduction abnormalities [14][15][16][17][18]. High resolution melting (HRM) is a mutation scanning technique that detects the progressive change in fluorescence caused by the release of an intercalating DNA dye from a DNA duplex as it is denatured by peripheral increases in temperature [19].…”

Section: Introductionmentioning

confidence: 99%