Recessive TAF1A mutations reveal ribosomopathy in siblings with end-stage pediatric dilated cardiomyopathy.

ABSTRACT: 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.

SUBMITTER: Long PA 

PROVIDER: S-EPMC6455043 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature