Predicting Phenotypic Severity of Uncertain Gene Variants in the RET Proto-Oncogene

Crockett, David K.; Piccolo, Stephen R.; Ridge, Perry G.; Margraf, Rebecca L.; Lyon, Elaine; Williams, Marc S.; Mitchell, Joyce A.

doi:10.1371/journal.pone.0018380

Cited by 33 publications

(29 citation statements)

References 28 publications

(49 reference statements)

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“…using the RET proto-oncogene as a model. However, this approach did not utilize nucleic-acid-based measurements and focused only on predicting phenotypic severity of uncertain gene variants [12]. …”

Section: Introductionmentioning

confidence: 99%

A Gene-Specific Method for Predicting Hemophilia-Causing Point Mutations

Hamasaki-Katagiri

Salari

et al. 2013

Journal of Molecular Biology

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A fundamental goal of medical genetics is the accurate prediction of genotype–phenotype correlations. As an approach to develop more accurate in silico tools for prediction of disease-causing mutations of structural proteins, we present a gene- and disease-specific prediction tool based on a large systematic analysis of missense mutations from hemophilia A (HA) patients. Our HA-specific prediction tool, HApredictor, showed disease prediction accuracy comparable to other publicly available prediction software. In contrast to those methods, its performance is not limited to non-synonymous mutations. Given the role of synonymous mutations in disease and drug codon optimization, we propose that utilizing a gene- and disease-specific method can be highly useful to make functional predictions possible even for synonymous mutations. Incorporating computational metrics at both nucleotide and amino acid levels along with multiple protein sequence/structure alignment significantly improved the predictive performance of our tool. HApredictor is freely available for download at http://www.ncbi.nlm.nih.gov/CBBresearch/Przytycka/HA_Predict/index.htm.

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Section: Introductionmentioning

confidence: 99%

A Gene-Specific Method for Predicting Hemophilia-Causing Point Mutations

Hamasaki-Katagiri

Salari

et al. 2013

Journal of Molecular Biology

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“…First, codon 666 of the RET gene encodes an evolutionarily conserved residue in the intracellular juxta-membrane domain of RET, and PolyPhen computational analysis predicts the change to be damaging (24). Second, in addition to the missense variant K666N, other variants at this codon have been reported to be associated with MTC (8-13).…”

Section: Discussionmentioning

confidence: 99%

“…First, of five established methods for analyzing mutation severity, including those measuring a RET genespecific Bayes probability classification, amino acid substitution penalties, structural disruption, sequence homology, and neural nets, only one classified K666N as pathogenic (24). Second, it is important to consider the example of the RET Y791F variant that was identified in MTC patients during extended gene analysis that included exon 13.…”

Section: Discussionmentioning

confidence: 99%

Medullary Thyroid Carcinoma Associated with Germline RET^K666N Mutation

Grubbs

Waguespack

et al. 2016

Thyroid

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Background: Multiple endocrine neoplasia type 2 is an autosomal dominant inherited syndrome caused by activating mutations in the RET proto-oncogene. The RET K666N DNA variant was previously reported in two isolated medullary thyroid carcinoma (MTC) cases, but no family studies are available, and its oncogenic significance remains unknown. Methods: The clinical features, genetic data, and family information of eight index MTC patients with a germline RET K666N variant were assessed. Results: Four probands presented with MTC and extensive nodal metastasis, one with biopsy-confirmed distant metastasis. Two additional probands presented with localized disease. However, nodal status was not available. Of the final two probands, one had an incidental 1.5 mm MTC and C-cell hyperplasia uncovered after surgery for papillary thyroid carcinoma, and one had two foci of MTC (largest dimension 2.3 cm) detected after surgery for dysphagia. Genetic screening identified 16 additional family members carrying the K666N variant (aged 5-90 years), 11 of whom have documented evaluation for MTC. Of these, only two were found to have elevated basal serum calcitonin upon screening, and the remaining patients had calcitonin levels within the reference range. One patient who elected to have a thyroidectomy at 70 years of age was confirmed to have MTC. The other subject, 57 years old, elected surveillance. Four prophylactic thyroidectomies were performed, with one case of C-cell hyperplasia at 20 years and three cases that revealed normal pathology at ages 21, 30, and 30 years. None of the K666N DNA variant carriers had evidence of primary hyperparathyroidism or pheochromocytoma. Conclusions: From this case series, the largest such experience to date, it is concluded that the RET K666N variant is likely pathogenic and associated with low penetrance of MTC. However, the findings are insufficient to define its pathogenicity clearly and make firm recommendations for screening and treatment. Given the potential benefit associated with early detection of aberrant C-cell growth, and the noninvasive nature of genetic testing, ''at risk'' individuals should be screened, and if the K666N variant is identified, they should be managed using a personalized screening approach for detection of MTC.

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“…Recently, a study evaluating the performance of on-line mutation prediction tools has been published [25]. However, only two out of five in silico prediction tools consider p.Ser649Leu as pathogenic or probably damaging mutation.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, p.Ser649Leu variant is known to be a MEN2 causative mutation resulting in a medium aggressive MTC [18]. In case of p.Ala641Ser, one out of five in silico tools predicted it as possibly pathogenic [25]. Association with MTC aggressiveness is harbored in ATA classification; mutations of the RET TMD are listed as "low risk", i.e.…”

Section: Discussionmentioning

confidence: 99%

Assessing the effect of RET Transmembrane Domain Mutations in receptor self-association capability using the in vivo TOXCAT System

Benej

Fekecsova²,

Poturnajova³

2012

neo

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Mutations of c-RET proto-oncogene with a unique localization within the human transmembrane receptor represent a challenge for contemporary molecular oncology techniques. RET transmembrane domain (TMD)-driven dimerization of the receptor leads to its permanent activation that eventually results in the development of medullary thyroid neoplasia. In this study, we describe the employment of the TOXCAT system which enables to investigate mutationinduced alterations in the strength of RET TMD dimerization in vivo. We suggest an improvement of the method by adding reporter gene quantification at the mRNA levels as a support to the commonly used reporter protein level. We have investigated possible changes in RET TMD dimerization in case of two germline RET TMD mutations found in in several individual cases and MEN2 families worldwide, p.Ala641Ser and p.Ser649Leu. According to our results, substitution of Ser-649 residue by leucine, found as a result of germline mutation, caused a significant decrease of RET TMD self-association in comparison to RET wild-type transmembrane domain. The impaired ability of self-association suggests a novel, yet unknown mechanism of tyrosine kinase domain activation, possibly independent of RET homodimerization. Key words: RET mutation, transmembrane domain, molecular oncology, TOXCAT system, oncoprotein dimerizationMedullary thyroid carcinoma (MTC) is a tumor that arises from parafollicular C cells located in the thyroid gland. Approximately 5-8% of all thyroid malignancies are represented by MTC [1]. The majority of MTC cases are sporadic, whereas 20-30% belong to the hereditary form [2]. Hereditary MTC is the most prevalent, hence obligatory manifestation of Multiple endocrine neoplasia type 2 (MEN 2) syndrome. The incidence of autosomal-dominant hereditary MEN 2 syndrome reaches 2.5 cases in 100 000 in general population [3]. MEN 2 syndrome is clinically divided into three distinct subtypes varying in the age of onset, rate of incidence, molecular-genetic mechanisms of onset and aggressiveness of MTC: MEN 2A, MEN 2B and familial MTC [4-6].Except for rare cases, MTC is triggered by germline mutations of a single allele of c-RET, a cellular proto-oncogene [7][8][9]. The gene encodes RET tyrosine kinase receptor, involved in signal transduction responsible for growth and differentiation in early stages of embryogenesis [10]. Mutations of the c-RET gene are divided into four risk levels, A-D, with the D level being the highest risk level [11]. The rationale for this classification lies in association of distinct mutations with specific aggressiveness of the MTC phenotype. Another classification is based on the position of specific mutation relative to the plasma membrane [12]. In both of these classifications, mutations of the transmembrane domain of RET protein are considered as a "low-risk" category.In most cases, the oncogenic transformation of c-RET is triggered by mutation-induced homodimerization of the RET receptor and by covalent linkage of the RET homodimer by disulfide bonds be...

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Predicting Phenotypic Severity of Uncertain Gene Variants in the RET Proto-Oncogene

Cited by 33 publications

References 28 publications

A Gene-Specific Method for Predicting Hemophilia-Causing Point Mutations

A Gene-Specific Method for Predicting Hemophilia-Causing Point Mutations

Medullary Thyroid Carcinoma Associated with Germline RET^K666N Mutation

Assessing the effect of RET Transmembrane Domain Mutations in receptor self-association capability using the in vivo TOXCAT System

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Predicting Phenotypic Severity of Uncertain Gene Variants in the RET Proto-Oncogene

Cited by 33 publications

References 28 publications

A Gene-Specific Method for Predicting Hemophilia-Causing Point Mutations

A Gene-Specific Method for Predicting Hemophilia-Causing Point Mutations

Medullary Thyroid Carcinoma Associated with Germline RETK666N Mutation

Assessing the effect of RET Transmembrane Domain Mutations in receptor self-association capability using the in vivo TOXCAT System

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Medullary Thyroid Carcinoma Associated with Germline RET^K666N Mutation