Recessive TAF1A mutations reveal ribosomopathy in siblings with end-stage pediatric dilated cardiomyopathy
- Long, P.A., Theis, J.L., Shih, Y.H., Maleszewski, J.J., Abell Aleff, P.C., Evans, J.M., Xu, X., Olson, T.M.
- Human molecular genetics 26(15): 2874-2881 (Journal)
- Registered Authors
- Shih, Yu-huan, Xu, Xiaolei
- cardiac myocyte, pericardial sac, phenotype, cardiomyopathy, dilated, heart transplantation, edema, mutation, heart failure, fibrosis, embryo, genes, heart ventricle, heterozygote, pediatrics, rna polymerase i, ribosomal rna, relationship - sibling, systole, zebrafish, diagnosis, heart, mortality, genetic screening, dilated cardiomyopathy, non-ischemic, end-stage heart failure, whole exome sequencing
- MeSH Terms
- Cardiomyopathy, Dilated/genetics*
- Child, Preschool
- Genetic Testing
- Heart Failure
- Mutation, Missense/genetics
- Myocytes, Cardiac/metabolism
- Pol1 Transcription Initiation Complex Proteins/genetics*
- Pol1 Transcription Initiation Complex Proteins/metabolism*
- RNA, Ribosomal/biosynthesis
- RNA, Ribosomal/genetics
- Whole Exome Sequencing
- 28472305 Full text @ Hum. Mol. Genet.
Long, P.A., Theis, J.L., Shih, Y.H., Maleszewski, J.J., Abell Aleff, P.C., Evans, J.M., Xu, X., Olson, T.M. (2017) Recessive TAF1A mutations reveal ribosomopathy in siblings with end-stage pediatric dilated cardiomyopathy. Human molecular genetics. 26(15):2874-2881.
Non-ischemic dilated cardiomyopathy (DCM) has been recognized as a heritable disorder for over 25 years, yet clinical genetic testing is non-diagnostic in > 50% of patients, underscoring the ongoing need for DCM gene discovery. Here, whole exome sequencing uncovered a novel molecular basis for idiopathic end-stage heart failure in two sisters who underwent cardiac transplantation at three years of age. Compound heterozygous recessive mutations in TAF1A, encoding an RNA polymerase I complex protein, were associated with marked fibrosis of explanted hearts and gene-specific nucleolar segregation defects in cardiomyocytes, indicative of impaired ribosomal RNA synthesis. Knockout of the homologous gene in zebrafish recapitulated a heart failure phenotype with pericardial edema, decreased ventricular systolic function, and embryonic mortality. These findings expand the clinical spectrum of ribosomopathies to include pediatric DCM.
Genes / Markers
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes