A Restricted Spectrum of Mutations in the SMAD4 Tumor-Suppressor Gene Underlies Myhre Syndrome

• Published in: American journal of human genetics Vol. 90; no. 1; pp. 161 - 169
• Main Authors: Caputo, Viviana, Cianetti, Luciano, Niceta, Marcello, Carta, Claudio, Ciolfi, Andrea, Bocchinfuso, Gianfranco, Carrani, Eugenio, Dentici, Maria Lisa, Biamino, Elisa, Belligni, Elga, Garavelli, Livia, Boccone, Loredana, Melis, Daniela, Andria, Generoso, Gelb, Bruce D., Stella, Lorenzo, Silengo, Margherita, Dallapiccola, Bruno, Tartaglia, Marco
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 13.01.2012; Cell Press; Elsevier
• Subjects: Adolescent; Adult; Base Sequence; Biological and medical sciences; Child, Preschool; Congenital diseases; Cryptorchidism - genetics; Exome - genetics; Facies; Female; Fundamental and applied biological sciences. Psychology; Gene expression; General aspects. Genetic counseling; Genetic research; Genetics of eukaryotes. Biological and molecular evolution; Growth Disorders - genetics; Hand Deformities, Congenital - genetics; Humans; Hypertrophy - genetics; Intellectual Disability - genetics; Joint Diseases - genetics; Male; Medical genetics; Medical sciences; Molecular and cellular biology; Molecular Sequence Data; Mutation; Mutation, Missense; Proteins; Signal transduction; Signal Transduction - genetics; Smad4 Protein - genetics; Tumors; Human; Genetics; Mutation; Tumor suppressor gene; Spectrum
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2011.12.011

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.