Left-right axis malformations associated with mutations inACVR2B, the gene for human activin receptor type IIB

Kosaki, Rika; Gebbia, Marinella; Kosaki, Kenjiro; Lewin, Mark B.; Bowers, Peter N.; Towbin, J.A.; Casey, Brett

doi:10.1002/(sici)1096-8628(19990101)82:1<70::aid-ajmg14>3.0.co;2-y

Cited by 187 publications

(103 citation statements)

References 26 publications

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“…Furthermore, no association was found with age at onset of the disease (data not shown). The E111E and N486N silent mutations were already found at high frequency in European and American populations by Kosaki et al (12) through the screening of the ACVR2B gene in normoglycemic patients with left-right axis malformations. It is noteworthy that we cannot exclude the presence of additional ACVR2B variations located in the promoter and introns in the MODY families tested.…”

mentioning

confidence: 99%

No Evidence for Linkage or for Diabetes-Associated Mutations in the Activin Type 2B Receptor Gene (ACVR2B) in French Patients With Mature-Onset Diabetes of the Young or Type 2 Diabetes

et al. 2001

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Activins are members of the transforming growth factor-␤ superfamily. They have a wide range of biological effects on cell growth and differentiation. For transmembrane signaling, activins bind directly to activin receptor type 2A (ACVR2A) or 2B (ACVR2B). Transgenic and knock-out mice for the ACVR2B gene display various endocrine pancreas-related abnormalities, including islet hypoplasia and glucose intolerance, demonstrating the crucial role of ACVR2B in the regulation of pancreas development. We have thus examined the contribution of this factor to the development of mature-onset diabetes of the young (MODY) and type 2 diabetes. No evidence of linkage at the ACVR2B locus has been detected in MODY families with unknown etiology for diabetes or found in affected sib pairs from families with type 2 diabetes. Mutation screening of the coding sequence in MODY probands and in a family with severe type 2 diabetes, including a case of pancreatic agenesis, showed single nucleotide polymorphisms that did not cosegregate with MODY and were not associated with type 2 diabetes. Our results indicate that ACVR2B does not represent a common cause of either MODY or type 2 diabetes in the French Caucasian population.

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mentioning

confidence: 99%

No Evidence for Linkage or for Diabetes-Associated Mutations in the Activin Type 2B Receptor Gene (ACVR2B) in French Patients With Mature-Onset Diabetes of the Young or Type 2 Diabetes

et al. 2001

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“…These results suggest that several genes may be involved in the patho- (12)(13)(14), mutations in genes affected in most patients remain unknown. Due to both asymmetric expression of HAND1 and cardiac specificity of NKX2-5, these two genes seem like to be candidate genes for atrial isomerism.…”

Section: Discussionmentioning

confidence: 99%

“…Nodal is one of these asymmetrically distributed secreted factors and Pitx2 is one of these asymmetrically expressed transcription factors (10,11). Some studies have demonstrated that human orthologue of the Nodal signaling genes, ACVR2B (12), LEFTYA (13) and CFC1 (14), were mutated in patients with heterotaxia. However, the etiology in most of the patients with laterality defects (heterotaxia syndromes) is thought to be chromosomal or polygenic-multifactorial, rather than monogenic.…”

Section: Introductionmentioning

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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“…This data shows that the Nodal signaling cascade within the lateral plate mesoderm is required for L-R patterning in vertebrates (Mercola and Levin, 2001;Hamada et al, 2002;Schier, 2003), and any disturbance in expression of NODAL can lead to polarity reversal of visceral organs and heart looping (Harvery, 1998). Mutations in NODAL have been identified in patients with heterotaxy following an autosomal dominant inheritance pattern (Kosaki et al, 1999;Bamford et al, 2000;Goldmuntz et al, 2002;Selamet Tierney et al, 2007;Roessler et al, 2008;Mohapatra et al, 2009). …”

Section: 52-nodal Leftya Cryptic and Acvr2bmentioning

confidence: 90%

Molecular Genetic Analysis of CRELD1 in Patients with Heterotaxy Disorder

Zhian¹

2000

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Heterotaxy refers to the abnormal arrangement of internal organs in relation to each other. Model organism studies have shown that functions of more than eighty genes are required for normal asymmetric left-right organ development. CRELD1 has been shown to be necessary for proper heart development and mutations in CRELD1 are known to increase risk of cardiac atrioventricular septal defects (AVSD). AVSD is the most common form of heart defect associated with heterotaxy, and we have previously shown that some individuals with heterotaxy-related AVSD have mutations in CRELD1.Therefore, we propose to examine the CRELD1 gene in a large sample of patients with heterotaxy syndrome. Our goal was to determine if mutations in CRELD1 are associated with other manifestations of heterotaxy or if they only coincide with AVSD. To achieve this aim, a sample size of 126 patients with heterotaxy collected by Dr. Belmont, Baylor college of Medicine, Texas, with approximately 66% of the heterotaxy population with different types of heart defects, were used for this study. Ten exons, promoter regions, and regulatory elements in the introns of CRELD1 gene were sequenced and analyzed.In this study three different heterozygous missense mutations in CRELD1 were identified in three unrelated individuals. These three individuals were diagnosed with different forms of heart defects in addition to AVSD. All three mutations were identified in highly conserved regions of CRELD1 possibly altering the CRELD1properties. This demonstrates that mutations in CRELD1 may increase the ii susceptibility of AVSD in heterotaxy population. This information can help us to find factors effecting disease susceptibility in heterotaxy patients since the heart defects are a complex trait with incomplete penetrance.iii iv Acknowledgements

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Left-right axis malformations associated with mutations inACVR2B, the gene for human activin receptor type IIB

Cited by 187 publications

References 26 publications

No Evidence for Linkage or for Diabetes-Associated Mutations in the Activin Type 2B Receptor Gene (ACVR2B) in French Patients With Mature-Onset Diabetes of the Young or Type 2 Diabetes

No Evidence for Linkage or for Diabetes-Associated Mutations in the Activin Type 2B Receptor Gene (ACVR2B) in French Patients With Mature-Onset Diabetes of the Young or Type 2 Diabetes

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

Molecular Genetic Analysis of CRELD1 in Patients with Heterotaxy Disorder

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