Repository of SMAD4 Mutations: Reference for Genotype/ Phenotype Correlation

Wooderchak, Whitney L.; Spencer, Zacary; Crockett, David K.; McDonald, Jamie; Bayrak-Toydemir, Pınar

doi:10.4172/2153-0602.1000101

Cited by 6 publications

(7 citation statements)

References 33 publications

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“…Also a large endoglin deletion was shown to convert from an exon 4–7 deletion to a de novo exon 3 deletion in one generation within a family. This was likely due to non-homologous end-joining (NHEJ) repair of a common breakpoint in ENG intron 3 ( Wooderchak et al, 2010b ). This finding has implications for molecular diagnostics since targeted family specific mutation analysis for exon deletions could have led to the misdiagnosis of some affected family members.…”

Section: Known Genes and Pathwaysmentioning

confidence: 99%

Hereditary hemorrhagic telangiectasia: genetics and molecular diagnostics in a new era

et al. 2015

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Hereditary hemorrhagic telangiectasia (HHT) is a vascular dysplasia characterized by telangiectases and arteriovenous malformations (AVMs) in particular locations described in consensus clinical diagnostic criteria published in 2000. Two genes in the transforming growth factor-beta (TGF-β) signaling pathway, ENG and ACVRL1, were discovered almost two decades ago, and mutations in these genes have been reported to cause up to 85% of HHT. In our experience, approximately 96% of individuals with HHT have a mutation in these two genes, when published (Curaçao) diagnostic criteria for HHT are strictly applied. More recently, two additional genes in the same pathway, SMAD4 and GDF2, have been identified in a much smaller number of patients with a similar or overlapping phenotype to HHT. Yet families still exist with compelling evidence of a hereditary telangiectasia disorder, but no identifiable mutation in a known gene. Recent availability of whole exome and genome testing has created new opportunities to facilitate gene discovery, identify genetic modifiers to explain clinical variability, and potentially define an increased spectrum of hereditary telangiectasia disorders. An expanded approach to molecular diagnostics for inherited telangiectasia disorders that incorporates a multi-gene next generation sequencing (NGS) HHT panel is proposed.

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Section: Known Genes and Pathwaysmentioning

confidence: 99%

Hereditary hemorrhagic telangiectasia: genetics and molecular diagnostics in a new era

et al. 2015

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“…The Department of Pathology at the University of Utah offers a manually curated database, hereon referred to as the ARUP database, of many known clinically significant mutations in SMAD4 Wooderchak et al (2010). The mutations identified are associated with JPS and with HHT.…”

Section: Smad2-smad4 Trimermentioning

confidence: 99%

“…Careful data gathering by researchers in the field (e.g. Wooderchak et al (2010)) has revealed that many missense mutations of SMAD4 are experimentally associated with juvenile polyposis syndrome (JPS) Howe et al (1998);Schwenter et al (2012), a hereditary disorder characterized by the formation of polyps in the rectum, colon or GI tract, and hereditary hemorrhagic telangiectasia (HHT) Gallione et al (2004Gallione et al ( , 2006, a different hereditary disorder that causes recurring nosebleeds, the dialation of capillaries in the mouth, face, hands, and GI tract, and venous malformation. We used charge-eliminating SMAD4 missense mutants as a benchmark to evaluate the accuracy of hypothetical mutation testing.…”

Section: Introductionmentioning

confidence: 99%

Influential Mutations in the SMAD4 Trimer Complex Can Be Detected from Disruptions of Electrostatic Complementarity

Nolan

Levenson

Chen

2017

Journal of Computational Biology

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This article examines three techniques for rapidly assessing the electrostatic contribution of individual amino acids to the stability of protein-protein complexes. Whereas the energetic minimization of modeled oligomers may yield more accurate complexes, we examined the possibility that simple modeling may be sufficient to identify amino acids that add to or detract from electrostatic complementarity. The three methods evaluated were (a) the elimination of entire side chains (e.g., glycine scanning), (b) the elimination of the electrostatic contribution from the atoms of a side chain, called nullification, and (c) side chain structure prediction using SCWRL4. These techniques generate models in seconds, enabling large-scale mutational scanning. We evaluated these techniques on the SMAD2/SMAD4 heterotrimer, whose formation plays a crucial role in antitumor pathways. Many studies have documented the clinical and structural effect of specific mutations on trimer formation. Our results describe how glycine scanning yields more specific predictions, although nullification may be more sensitive, and how side chain structure prediction enables the identification of uncharged-to-charge mutations.

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“…Inherited mutations in the CDH1 gene increase a woman's risk of developing a form of breast cancer that begins in the milk-producing glands (lobular breast cancer) [36]. In many cases, this increased risk occurs as part of a cancer syndrome called hereditary diffuse gastric cancer (HDGC) [37]. This condition is characterized by a very high risk of developing cancer of the stomach lining as well as an increased risk of lobular breast cancer.…”

Section: Cdhimentioning

confidence: 99%

Epidemiology of Genetic Alterations in Progression of Breast Cancer

P¹

2012

J Carcinogene Mutagene

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Breast cancer is the most frequent cancer in women responsible for almost 20% of all cancer deaths. Certain aberrations in the genes results higher risk in the development of breast cancer. The present review aims to consolidate a comprehensive role of different genes involved in the development of breast cancer. This helps to know the intracellular molecular changes in tumorigenic pathways within the mammary gland.

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Repository of SMAD4 Mutations: Reference for Genotype/ Phenotype Correlation

Cited by 6 publications

References 33 publications

Hereditary hemorrhagic telangiectasia: genetics and molecular diagnostics in a new era

Hereditary hemorrhagic telangiectasia: genetics and molecular diagnostics in a new era

Influential Mutations in the SMAD4 Trimer Complex Can Be Detected from Disruptions of Electrostatic Complementarity

Epidemiology of Genetic Alterations in Progression of Breast Cancer

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