Details

Autor(en) / Beteiligte

• Long, Pamela A
• Theis, Jeanne L
• Shih, Yu-Huan
• Maleszewski, Joseph J
• Abell Aleff, Patrice C
• Evans, Jared M
• Xu, Xiaolei
• Olson, Timothy M

Titel

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

Ist Teil von

• Human molecular genetics, 2017-08, Vol.26 (15), p.2874-2881

Ort / Verlag

England: Oxford University Press

Erscheinungsjahr

2017

Link zum Volltext

Quelle

Oxford Journals 2020 Medicine

Beschreibungen/Notizen

• 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.