Protein molecular modeling techniques investigating novel TAB2 variant R347X causing cardiomyopathy and congenital heart defects in multigenerational family

Autor: Thomas R. Caulfield, John E. Richter, Emily E. Brown, Paldeep S. Atwal, Ahmed N. Mohammad, Daniel P. Judge
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Zdroj: Molecular Genetics & Genomic Medicine
ISSN: 2324-9269
Popis: Background: \ud Haploinsufficiency of TAB 2 is known to cause congenital heart defects and cardiomyopathy due to its important roles in cardiovascular tissue, both during development and through adult life. We report a sibling pair displaying adult‐onset cardiomyopathy, hypermobility, and mild myopia. Our proband, a 39‐year‐old male, presents only with the above symptoms, while his 36‐year‐old sister was also notable for a ventricular septal defect in her infancy.\ud \ud Methods: \ud Whole‐exome sequencing was utilized to identify the molecular basis of the phenotype found in two siblings. A molecular modeling technique that takes advantage of conformational sampling advances (Maxwell's demon molecular dynamics and Monte Carlo) were used to make a model of the mutant variant for comparative analytics to the wild‐type.\ud \ud Results: \ud Exome sequencing revealed a novel, heterogeneous pathogenic variant in TAB 2 , c.1039 C>T (p.R347X), that was present in both individuals. This pathogenic variant removes just over half the residues from the TAB 2 protein and severely impacts its functional ability, which we describe in detail.\ud \ud Conclusions: \ud Analysis of the proband's family showed a history of cardiomyopathy, but no congenital heart defects or connective tissue disease. We highlight the heterogeneity in phenotype of TAB 2 pathogenic variants and confirm the pathogenicity of this new variant through neoteric protein modeling techniques.
Databáze: OpenAIRE
Externí odkaz: