A case report of recessive restrictive cardiomyopathy caused by a novel mutation in cardiac troponin I (TNNI3).

BACKGROUND: Restrictive cardiomyopathy is a rare cardiac disease, for which several genes including TNNT2, MYPN, FLNC and TNNI3 have been associated with its familial form. CASE PRESENTATION: Here we describe a female proband with a severely manifested restrictive phenotype leading to heart transplantation at the age of 41, who was found homozygous for the novel TNNI3 mutation: NM_000363.4:c.586G > C, p.(Asp196His). Her parents were third-degree cousins originating from a small village and although they were found heterozygous for the same variant they displayed no symptoms of the disease. Her older sister who was also found heterozygous was asymptomatic. Her twin sister and her brother who were homozygous for the same variant displayed a restrictive and a hypertrophic phenotype, respectively. Their children are all carriers of the mutation and remain asymptomatic until the age of 21. CONCLUSION: These observations point to a recessive mode of inheritance reported for the first time for this combination of gene/disease.

A new phenotype of severe dilated cardiomyopathy associated with a mutation in the LAMP2 gene previously known to cause hypertrophic cardiomyopathy in the context of Danon disease.

Danon disease is a rare X-linked cardiac and skeletal muscle disorder with multisystem clinical manifestations. Genetic defects at the lysosome-associated membrane 2 protein (LAMP2) are the cause of the disorder. Due to the rarity of the disease, there is limited progress in understanding the correlation between genotype and phenotype, and explaining the large variability of the clinical features of the disease. In this study, we report two patients, twin sisters, referred to our hospital for end stage heart failure due to dilated cardiomyopathy, requiring heart transplant evaluation. Genetic analysis, using targeted next generation sequencing, showed that the proband carried a LAMP2 missense variant, c.928G > A. The mutation was also detected in her twin sister by sanger sequencing. This variant has already been reported by other investigators and was correlated with the clinical triad of Danon disease i.e. hypertrophic cardiomyopathy, mental retardation and peripheral myopathy. The new phenotype of dilated cardiomyopathy associated with this mutation, confirms the phenotypic heterogeneity of the particular mutation, as well as of Danon disease.

Phenotypic Heterogeneity within Members of a Family Carrying the Same RBM20 Mutation R634W.

OBJECTIVE: We present the genotypic and phenotypic characterization of a family displaying dilated cardiomyopathy (DCM). METHODS: The proband and his relatives underwent full cardiological assessment. Genetic analysis of the proband was performed with the use of next-generation sequencing technology. RESULTS: In this study, we present 6 members of a family carrying the RBM20 mutation NM_001134363.2:c.1900C>T. The proband was initially diagnosed with DCM at the age of 18 years and received an implantable cardioverter defibrillator (ICD) due to ventricular arrhythmias. His brother, carrier of the mutation, has been diagnosed with borderline left ventricular function. The mutation was shown to be of paternal origin, but their father remains asymptomatic with a mild DCM, while his electrocardiogram at the initial evaluation showed a right bundle branch block pattern. The mutation was also detected in the index case's aunt who was resuscitated from sudden cardiac death. Her echocardiography revealed early stages of DCM and a bicuspid aortic valve. Her children are both carriers of the mutation. Her daughter is unaffected, but her son has an ICD implanted due to sustained ventricular tachycardia and presents early signs of DCM. CONCLUSION: Our findings are the first report of co-segregation of the mutation in 6 family members, supporting its pathogenic role.

Quantitative online prediction of peptide binding to the major histocompatibility complex.

With its implications for vaccine discovery, the accurate prediction of T cell epitopes is one of the key aspirations of computational vaccinology. We have developed a robust multivariate statistical method, based on partial least squares, for the quantitative prediction of peptide binding to major histocompatibility complexes (MHC), the principal checkpoint on the antigen presentation pathway. As a service to the immunobiology community, we have made a Perl implementation of the method available via a World Wide Web server. We call this server MHCPred. Access to the server is freely available from the URL: http://www.jenner.ac.uk/MHCPred. We have exemplified our method with a model for peptides binding to the common human MHC molecule HLA-B*3501.

JenPep: a novel computational information resource for immunobiology and vaccinology.

JenPep is a relational database containing a compendium of thermodynamic binding data for the interaction of peptides with a range of important immunological molecules: the major histocompatibility complex, TAP transporter, and T cell receptor. The database also includes annotated lists of B cell and T cell epitopes. Version 2.0 of the database is implemented in a bespoke postgreSQL database system and is fully searchable online via a perl/HTML interface (URL: http://www.jenner.ac.uk/JenPep).

MHCPred: A server for quantitative prediction of peptide-MHC binding.

Accurate T-cell epitope prediction is a principal objective of computational vaccinology. As a service to the immunology and vaccinology communities at large, we have implemented, as a server on the World Wide Web, a partial least squares-based multivariate statistical approach to the quantitative prediction of peptide binding to major histocom- patibility complexes (MHC), the key checkpoint on the antigen presentation pathway within adaptive cellular immunity. MHCPred implements robust statistical models for both Class I alleles (HLA-A*0101, HLA-A*0201, HLA-A*0202, HLA-A*0203, HLA-A*0206, HLA-A*0301, HLA-A*1101, HLA-A*3301, HLA-A*6801, HLA-A*6802 and HLA-B*3501) and Class II alleles (HLA-DRB*0401, HLA-DRB*0401 and HLA-DRB*0701). MHCPred is available from the URL: http://www.jenner.ac.uk/MHCPred.

MHCPred: bringing a quantitative dimension to the online prediction of MHC binding.

The accurate prediction of T cell epitopes is one of the key aspirations of immunoinformatics. We have developed a partial least squares-based, robust multivariate statistical method for the quantitative prediction of peptide binding to major histocompatibility complexes (MHCs), the principal checkpoint on the antigen presentation pathway. As a service to the immunobiology community, we have made a Perl implementation of the method available as a World Wide Web server.

Computational vaccinology: quantitative approaches.

The immune system is hierarchical and has many levels, exhibiting much emergent behaviour. However, at its heart are molecular recognition events that are indistinguishable from other types of biomacromolecular interaction. These can be addressed well by quantitative experimental and theoretical biophysical techniques, and particularly by methods from drug design. We review here our approach to computational immunovaccinology. In particular, we describe the JenPep database and two new techniques for T cell epitope prediction. One is based on quantitative structure-activity relationships (a 3D-QSAR method based on CoMSIA and another 2D method based on the Free-Wilson approach) and the other on atomistic molecular dynamic simulations using high performance computing. JenPep (http://www.jenner.ar.uk/ JenPep) is a relational database system supporting quantitative data on peptide binding to major histocompatibility complexes, TAP transporters, TCR-pMHC complexes, and an annotated list of B cell and T cell epitopes. Our 2D-QSAR method factors the contribution to peptide binding from individual amino acids as well as 1-2 and 1-3 residue interactions. In the 3D-QSAR approach, the influence of five physicochemical properties (volume, electrostatic potential, hydrophobicity, hydrogen-bond donor and acceptor abilities) on peptide affinity were considered. Both methods are exemplified through their application to the well-studied problem of peptide binding to the human class I MHC molecule HLA-A*0201.