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

Caulfield, T. R., Richter Jr., J. E., Brown, E. E., Mohammad, A. N., Judge, D. P. and Atwal, P. S. (2018) Protein molecular modeling techniques investigating novel TAB2 variant R347X causing cardiomyopathy and congenital heart defects in multigenerational family. Molecular Genetics and Genomic Medicine, 6(4), pp. 666-672. (doi: 10.1002/mgg3.401) (PMID:29700987) (PMCID:PMC6081229)

Abstract

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Atwal, Dr Paldeep
• Authors: Caulfield, T. R., Richter Jr., J. E., Brown, E. E., Mohammad, A. N., Judge, D. P., and Atwal, P. S.
• College/School: College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Journal Name: Molecular Genetics and Genomic Medicine
• Publisher: Wiley
• ISSN: 2324-9269
• ISSN (Online): 2324-9269
• Published Online: 26 April 2018
• Copyright Holders: Copyright © 2018 The Authors
• First Published: First published in Molecular Genetics and Genomic Medicine 6(4): 666-672
• Publisher Policy: Reproduced under a Creative Commons License