A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2

Nat Genet. 2005 Mar;37(3):275-81. doi: 10.1038/ng1511. Epub 2005 Jan 30.

Abstract

We report heterozygous mutations in the genes encoding either type I or type II transforming growth factor beta receptor in ten families with a newly described human phenotype that includes widespread perturbations in cardiovascular, craniofacial, neurocognitive and skeletal development. Despite evidence that receptors derived from selected mutated alleles cannot support TGFbeta signal propagation, cells derived from individuals heterozygous with respect to these mutations did not show altered kinetics of the acute phase response to administered ligand. Furthermore, tissues derived from affected individuals showed increased expression of both collagen and connective tissue growth factor, as well as nuclear enrichment of phosphorylated Smad2, indicative of increased TGFbeta signaling. These data definitively implicate perturbation of TGFbeta signaling in many common human phenotypes, including craniosynostosis, cleft palate, arterial aneurysms, congenital heart disease and mental retardation, and suggest that comprehensive mechanistic insight will require consideration of both primary and compensatory events.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Activin Receptors, Type I / genetics*
  • Amino Acid Sequence
  • Bone Development / genetics*
  • Cardiovascular System / growth & development*
  • Child, Preschool
  • Cognition Disorders / genetics*
  • Face*
  • Female
  • Humans
  • Male
  • Molecular Sequence Data
  • Mutation*
  • Phenotype
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / genetics*
  • Sequence Homology, Amino Acid
  • Skull / growth & development*
  • Syndrome

Substances

  • Receptors, Transforming Growth Factor beta
  • Protein-Serine-Threonine Kinases
  • Activin Receptors, Type I
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptor, Transforming Growth Factor-beta Type II
  • TGFBR1 protein, human

Associated data

  • RefSeq/NM_003242
  • RefSeq/NM_004612
  • RefSeq/NT_022517
  • RefSeq/NT_086754