Recessive TAF1A mutations reveal ribosomopathy in siblings with end-stage pediatric dilated cardiomyopathy.
Hum Mol Genet
; 26(15): 2874-2881, 2017 08 01.
Article
em En
| MEDLINE
| ID: mdl-28472305
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.
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
2_ODS3
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6_ODS3_enfermedades_notrasmisibles
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7_ODS3_muertes_prevenibles_nacidos_ninos
Base de dados:
MEDLINE
Assunto principal:
Cardiomiopatia Dilatada
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Proteínas Pol1 do Complexo de Iniciação de Transcrição
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Child
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Child, preschool
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Female
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Humans
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Male
Idioma:
En
Revista:
Hum Mol Genet
Ano de publicação:
2017
Tipo de documento:
Article