TY - JOUR
T1 - A restricted spectrum of mutations in the SMAD4 tumor-suppressor gene underlies myhre syndrome
AU - Caputo, Viviana
AU - Cianetti, Luciano
AU - Niceta, Marcello
AU - Carta, Claudio
AU - Ciolfi, Andrea
AU - Bocchinfuso, Gianfranco
AU - Carrani, Eugenio
AU - Dentici, Maria Lisa
AU - Biamino, Elisa
AU - Belligni, Elga
AU - Garavelli, Livia
AU - Boccone, Loredana
AU - Melis, Daniela
AU - Andria, Generoso
AU - Gelb, Bruce D.
AU - Stella, Lorenzo
AU - Silengo, Margherita
AU - Dallapiccola, Bruno
AU - Tartaglia, Marco
N1 - Funding Information:
We are indebted to the families who participated in the study, the physicians who referred the subjects, and Valentina Fodale, Francesca Pantaleoni, Viviana Cordeddu, and Serenella Venanzi (Istituto Superiore di Sanità, Rome, Italy) for experimental support. We thank the colleagues at the SIDBAE (Istituto Superiore di Sanità) for information technology support. This research was funded by grants from Telethon-Italy (GGP10020), Associazione Italiana per la Ricerca sul Cancro Investigator Grant 2009 (8803), and “Collaborazione Italia-USA” to M.T, and Italian Ministry of Health (Ricerca Corrente 2011) to B.D and M.T.
PY - 2012/1/13
Y1 - 2012/1/13
N2 - Myhre syndrome is a developmental disorder characterized by reduced growth, generalized muscular hypertrophy, facial dysmorphism, deafness, cognitive deficits, joint stiffness, and skeletal anomalies. Here, by performing exome sequencing of a single affected individual and coupling the results to a hypothesis-driven filtering strategy, we establish that heterozygous mutations in SMAD4, which encodes for a transducer mediating transforming growth factor β and bone morphogenetic protein signaling branches, underlie this rare Mendelian trait. Two recurrent de novo SMAD4 mutations were identified in eight unrelated subjects. Both mutations were missense changes altering Ile500 within the evolutionary conserved MAD homology 2 domain, a well known mutational hot spot in malignancies. Structural analyses suggest that the substituted residues are likely to perturb the binding properties of the mutant protein to signaling partners. Although SMAD4 has been established as a tumor suppressor gene somatically mutated in pancreatic, gastrointestinal, and skin cancers, and germline loss-of-function lesions and deletions of this gene have been documented to cause disorders that predispose individuals to gastrointestinal cancer and vascular dysplasias, the present report identifies a previously unrecognized class of mutations in the gene with profound impact on development and growth.
AB - Myhre syndrome is a developmental disorder characterized by reduced growth, generalized muscular hypertrophy, facial dysmorphism, deafness, cognitive deficits, joint stiffness, and skeletal anomalies. Here, by performing exome sequencing of a single affected individual and coupling the results to a hypothesis-driven filtering strategy, we establish that heterozygous mutations in SMAD4, which encodes for a transducer mediating transforming growth factor β and bone morphogenetic protein signaling branches, underlie this rare Mendelian trait. Two recurrent de novo SMAD4 mutations were identified in eight unrelated subjects. Both mutations were missense changes altering Ile500 within the evolutionary conserved MAD homology 2 domain, a well known mutational hot spot in malignancies. Structural analyses suggest that the substituted residues are likely to perturb the binding properties of the mutant protein to signaling partners. Although SMAD4 has been established as a tumor suppressor gene somatically mutated in pancreatic, gastrointestinal, and skin cancers, and germline loss-of-function lesions and deletions of this gene have been documented to cause disorders that predispose individuals to gastrointestinal cancer and vascular dysplasias, the present report identifies a previously unrecognized class of mutations in the gene with profound impact on development and growth.
UR - http://www.scopus.com/inward/record.url?scp=84855858089&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2011.12.011
DO - 10.1016/j.ajhg.2011.12.011
M3 - Article
C2 - 22243968
AN - SCOPUS:84855858089
SN - 0002-9297
VL - 90
SP - 161
EP - 169
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 1
ER -