title: A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2.
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.
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Bart L
authors.initials: BL
authors.lastname: Loeys
authors.forename: Junji
authors.initials: J
authors.lastname: Chen
authors.forename: Enid R
authors.initials: ER
authors.lastname: Neptune
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Judge
authors.forename: Megan
authors.initials: M
authors.lastname: Podowski
authors.forename: Tammy
authors.initials: T
authors.lastname: Holm
authors.forename: Jennifer
authors.initials: J
authors.lastname: Meyers
authors.forename: Carmen C
authors.initials: CC
authors.lastname: Leitch
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.forename: Neda
authors.initials: N
authors.lastname: Sharifi
authors.forename: F Lauren
authors.initials: FL
authors.lastname: Xu
authors.forename: Loretha A
authors.initials: LA
authors.lastname: Myers
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Spevak
authors.forename: Duke E
authors.initials: DE
authors.lastname: Cameron
authors.forename: Julie
authors.initials: J
authors.lastname: De Backer
authors.forename: Jan
authors.initials: J
authors.lastname: Hellemans
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: Elaine C
authors.initials: EC
authors.lastname: Davis
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Webb
authors.forename: Wolfram
authors.initials: W
authors.lastname: Kress
authors.forename: Paul
authors.initials: P
authors.lastname: Coucke
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Rifkin
authors.forename: Anne M
authors.initials: AM
authors.lastname: De Paepe
authors.forename: Harry C
authors.initials: HC
authors.lastname: Dietz
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics*; D000595:Amino Acid Sequence; D001846:Bone Development / Q000235:genetics*; D002319:Cardiovascular System / Q000254:growth & development*; D002675:Child, Preschool; D003072:Cognition Disorders / Q000235:genetics*; D005145:Face; D005260:Female; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D012886:Skull / Q000254:growth & development*; D013577:Syndrome
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; C000625841:TGFBR1 protein, human