hnRNP U protein is required for normal pre-mRNA splicing and postnatal heart development and function

Proc Natl Acad Sci U S A. 2015 Jun 9;112(23):E3020-9. doi: 10.1073/pnas.1508461112. Epub 2015 May 26.


We report that mice lacking the heterogeneous nuclear ribonucleoprotein U (hnRNP U) in the heart develop lethal dilated cardiomyopathy and display numerous defects in cardiac pre-mRNA splicing. Mutant hearts have disorganized cardiomyocytes, impaired contractility, and abnormal excitation-contraction coupling activities. RNA-seq analyses of Hnrnpu mutant hearts revealed extensive defects in alternative splicing of pre-mRNAs encoding proteins known to be critical for normal heart development and function, including Titin and calcium/calmodulin-dependent protein kinase II delta (Camk2d). Loss of hnRNP U expression in cardiomyocytes also leads to aberrant splicing of the pre-mRNA encoding the excitation-contraction coupling component Junctin. We found that the protein product of an alternatively spliced Junctin isoform is N-glycosylated at a specific asparagine site that is required for interactions with specific protein partners. Our findings provide conclusive evidence for the essential role of hnRNP U in heart development and function and in the regulation of alternative splicing.

Keywords: N-glycosylation; RNA-seq; alternative splicing; dilated cardiomyopathy; heart development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing / physiology*
  • Animals
  • Calcium / metabolism
  • Calcium-Binding Proteins / metabolism
  • Glycosylation
  • Heart / growth & development*
  • Heart / physiology*
  • Heterogeneous-Nuclear Ribonucleoprotein U / genetics
  • Heterogeneous-Nuclear Ribonucleoprotein U / physiology*
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Mixed Function Oxygenases / metabolism
  • Muscle Proteins / metabolism
  • Mutation
  • RNA Precursors / metabolism*
  • RNA, Messenger / metabolism*
  • Sarcomeres / metabolism


  • Calcium-Binding Proteins
  • Heterogeneous-Nuclear Ribonucleoprotein U
  • Membrane Proteins
  • Muscle Proteins
  • RNA Precursors
  • RNA, Messenger
  • Asph protein, mouse
  • Mixed Function Oxygenases
  • Calcium

Associated data

  • GEO/GSE68178