title: A restricted spectrum of mutations in the SMAD4 tumor-suppressor gene underlies Myhre syndrome.
abstract: 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.
authors.affiliation: Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Viviana
authors.initials: V
authors.lastname: Caputo
authors.forename: Luciano
authors.initials: L
authors.lastname: Cianetti
authors.forename: Marcello
authors.initials: M
authors.lastname: Niceta
authors.forename: Claudio
authors.initials: C
authors.lastname: Carta
authors.forename: Andrea
authors.initials: A
authors.lastname: Ciolfi
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Bocchinfuso
authors.forename: Eugenio
authors.initials: E
authors.lastname: Carrani
authors.forename: Maria Lisa
authors.initials: ML
authors.lastname: Dentici
authors.forename: Elisa
authors.initials: E
authors.lastname: Biamino
authors.forename: Elga
authors.initials: E
authors.lastname: Belligni
authors.forename: Livia
authors.initials: L
authors.lastname: Garavelli
authors.forename: Loredana
authors.initials: L
authors.lastname: Boccone
authors.forename: Daniela
authors.initials: D
authors.lastname: Melis
authors.forename: Generoso
authors.initials: G
authors.lastname: Andria
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Gelb
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Stella
authors.forename: Margherita
authors.initials: M
authors.lastname: Silengo
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
authors.forename: Marco
authors.initials: M
authors.lastname: Tartaglia
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002675:Child, Preschool; D003456:Cryptorchidism / Q000235:genetics*; D059472:Exome / Q000235:genetics; D019066:Facies; D005260:Female; D006130:Growth Disorders / Q000235:genetics*; D006228:Hand Deformities, Congenital / Q000235:genetics*; D006801:Humans; D006984:Hypertrophy / Q000235:genetics*; D008607:Intellectual Disability / Q000235:genetics*; D007592:Joint Diseases / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D015398:Signal Transduction / Q000235:genetics; D051901:Smad4 Protein / Q000235:genetics*
chemical_list: C497796:SMAD4 protein, human; D051901:Smad4 Protein