Congenital asplenia in mice and humans with mutations in a Pbx/Nkx2-5/p15 module

Dev Cell. 2012 May 15;22(5):913-26. doi: 10.1016/j.devcel.2012.02.009. Epub 2012 May 3.

Abstract

The molecular determinants of spleen organogenesis and the etiology of isolated congenital asplenia (ICA), a life-threatening human condition, are unknown. We previously reported that Pbx1 deficiency causes organ growth defects including asplenia. Here, we show that mice with splenic mesenchyme-specific Pbx1 inactivation exhibit hyposplenia. Moreover, the loss of Pbx causes downregulation of Nkx2-5 and derepression of p15Ink4b in spleen mesenchymal progenitors, perturbing the cell cycle. Removal of p15Ink4b in Pbx1 spleen-specific mutants partially rescues spleen growth. By whole-exome sequencing of a multiplex kindred with ICA, we identify a heterozygous missense mutation (P236H) in NKX2-5 showing reduced transactivation in vitro. This study establishes that a Pbx/Nkx2-5/p15 regulatory module is essential for spleen development.

Publication types

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

MeSH terms

  • Adolescent
  • Amino Acid Sequence
  • Animals
  • Cells, Cultured
  • Cyclin-Dependent Kinase Inhibitor p15 / metabolism
  • DNA-Binding Proteins / deficiency
  • Exome
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental
  • Homeobox Protein Nkx-2.5
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Humans
  • Infant
  • Male
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • Mutation, Missense
  • Pedigree
  • Pre-B-Cell Leukemia Transcription Factor 1
  • Proto-Oncogene Proteins / deficiency
  • Spleen / abnormalities*
  • Splenic Diseases / genetics*
  • Transcription Factors / deficiency
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism

Substances

  • CDKN2B protein, human
  • Cdkn2b protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p15
  • DNA-Binding Proteins
  • Homeobox Protein Nkx-2.5
  • Homeodomain Proteins
  • NKX2-5 protein, human
  • Nkx2-5 protein, mouse
  • Pbx1 protein, mouse
  • Pre-B-Cell Leukemia Transcription Factor 1
  • Proto-Oncogene Proteins
  • Transcription Factors
  • pbx1 protein, human