ArticleProceedings of the National Academy of Sciences of the United States of America2005
Phenotype-genotype correlation in Hirschsprung disease is illuminated by comparative analysis of the RET protein sequence.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
19 citing papers in PubMed, 39 citations in OpenAlex.
- RET receptor tyrosine kinase architecture, assemblies, and activation.Endocrine-related cancer · 2026Review
- Systematic structure-based analysis of RET variants in MEN2A and Hirschsprung's disease, and the paradoxical co-occurrence of both conditions.Disease models & mechanisms · 2026Article
- Variability in proliferative and migratory defects in Hirschsprung disease-associated RET pathogenic variants.American journal of human genetics · 2025Article
- Variability in proliferative and migratory defects in Hirschsprung disease-associatedbioRxiv : the preprint server for biology · 2024Article
- Identification of New Potential LncRNA Biomarkers in Hirschsprung Disease.International journal of molecular sciences · 2020Article
- Aminode: Identification of Evolutionary Constraints in the Human Proteome.Scientific reports · 2018Article
- Identification of a novel variant of the RET proto-oncogene in a novel family with Hirschsprung's disease.Pediatric surgery international · 2017Article
- Hirschsprung's disease: clinical dysmorphology, genes, micro-RNAs, and future perspectives.Pediatric research · 2017Review
- Male and female differential reproductive rate could explain parental transmission asymmetry of mutation origin in Hirschsprung disease.European journal of human genetics : EJHG · 2012Article
- Hirschsprung's disease and variants in genes that regulate enteric neural crest cell proliferation, migration and differentiation.Journal of human genetics · 2012Article
- Predicting functionally important SNP classes based on negative selection.BMC bioinformatics · 2011Article
- Differential contributions of rare and common, coding and noncoding Ret mutations to multifactorial Hirschsprung disease liability.American journal of human genetics · 2010Article
- Mammal-restricted elements predispose human RET to folding impairment by HSCR mutations.Nature structural & molecular biology · 2010Article
- ProPhylER: a curated online resource for protein function and structure based on evolutionary constraint analyses.Genome research · 2010Article
- Article
- Genetic basis of Hirschsprung's disease.Pediatric surgery international · 2009Review
- Domain duplication, divergence, and loss events in vertebrate Msx paralogs reveal phylogenomically informed disease markers.BMC evolutionary biology · 2009Article
- An investigation of genome-wide associations of hypertension with microsatellite markers in the family blood pressure program (FBPP).Human genetics · 2007Article
- Self-association of the transmembrane domain of RET underlies oncogenic activation by MEN2A mutations.Oncogene · 2006Article
Corrections and comments
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Authors and funding
8 authors at 4 institutions in 1 country.
Funding
Abstract
The ability to discriminate between deleterious and neutral amino acid substitutions in the genes of patients remains a significant challenge in human genetics. The increasing availability of genomic sequence data from multiple vertebrate species allows inclusion of sequence conservation and physicochemical properties of residues to be used for functional prediction. In this study, the RET receptor tyrosine kinase serves as a model disease gene in which a broad spectrum (> or = 116) of disease-associated mutations has been identified among patients with Hirschsprung disease and multiple endocrine neoplasia type 2. We report the alignment of the human RET protein sequence with the orthologous sequences of 12 non-human vertebrates (eight mammalian, one avian, and three teleost species), their comparative analysis, the evolutionary topology of the RET protein, and predicted tolerance for all published missense mutations. We show that, although evolutionary conservation alone provides significant information to predict the effect of a RET mutation, a model that combines comparative sequence data with analysis of physiochemical properties in a quantitative framework provides far greater accuracy. Although the ability to discern the impact of a mutation is imperfect, our analyses permit substantial discrimination between predicted functional classes of RET mutations and disease severity even for a multigenic disease such as Hirschsprung disease.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.