A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2.
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.
Loeys
Bart L
BL
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Chen
Junji
J
Neptune
Enid R
ER
Judge
Daniel P
DP
Podowski
Megan
M
Holm
Tammy
T
Meyers
Jennifer
J
Leitch
Carmen C
CC
Katsanis
Nicholas
N
Sharifi
Neda
N
Xu
F Lauren
FL
Myers
Loretha A
LA
Spevak
Philip J
PJ
Cameron
Duke E
DE
De Backer
Julie
J
Hellemans
Jan
J
Chen
Yan
Y
Davis
Elaine C
EC
Webb
Catherine L
CL
Kress
Wolfram
W
Coucke
Paul
P
Rifkin
Daniel B
DB
De Paepe
Anne M
AM
Dietz
Harry C
HC
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
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