ZFIN ID: ZDB-PUB-170505-2
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.
Date: 2017
Source: Human molecular genetics   26(15): 2874-2881 (Journal)
Registered Authors: Shih, Yu-huan, Xu, Xiaolei
Keywords: 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:
  • Animals
  • Cardiomyopathy, Dilated/genetics*
  • Child
  • Child, Preschool
  • Exome
  • Female
  • Fibrosis/genetics
  • Genetic Testing
  • Heart Failure
  • Heterozygote
  • Humans
  • Male
  • Mutation
  • Mutation, Missense/genetics
  • Myocytes, Cardiac/metabolism
  • Pedigree
  • Pol1 Transcription Initiation Complex Proteins/genetics*
  • Pol1 Transcription Initiation Complex Proteins/metabolism*
  • RNA, Ribosomal/biosynthesis
  • RNA, Ribosomal/genetics
  • Siblings
  • Whole Exome Sequencing
  • Zebrafish/genetics
PubMed: 28472305 Full text @ Hum. Mol. Genet.
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.