title: Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome.
abstract: Myhre syndrome (MIM 139210) is a developmental disorder characterized by short stature, short hands and feet, facial dysmorphism, muscular hypertrophy, deafness and cognitive delay. Using exome sequencing of individuals with Myhre syndrome, we identified SMAD4 as a candidate gene that contributes to this syndrome on the basis of its pivotal role in the bone morphogenetic pathway (BMP) and transforming growth factor (TGF)-β signaling. We identified three distinct heterozygous missense SMAD4 mutations affecting the codon for Ile500 in 11 individuals with Myhre syndrome. All three mutations are located in the region of SMAD4 encoding the Mad homology 2 (MH2) domain near the site of monoubiquitination at Lys519, and we found a defect in SMAD4 ubiquitination in fibroblasts from affected individuals. We also observed decreased expression of downstream TGF-β target genes, supporting the idea of impaired TGF-β-mediated transcriptional control in individuals with Myhre syndrome.
authors.affiliation: Département de Génétique, Unité INSERM U781, Université Paris Descartes, Sorbonne Paris Cité, Hôpital Necker Enfants Malades, Paris, France.
authors.forename: Carine
authors.initials: C
authors.lastname: Le Goff
authors.forename: Clémentine
authors.initials: C
authors.lastname: Mahaut
authors.forename: Avinash
authors.initials: A
authors.lastname: Abhyankar
authors.forename: Wilfried
authors.initials: W
authors.lastname: Le Goff
authors.forename: Valérie
authors.initials: V
authors.lastname: Serre
authors.forename: Alexandra
authors.initials: A
authors.lastname: Afenjar
authors.forename: Anne
authors.initials: A
authors.lastname: Destrée
authors.forename: Maja
authors.initials: M
authors.lastname: di Rocco
authors.forename: Delphine
authors.initials: D
authors.lastname: Héron
authors.forename: Sébastien
authors.initials: S
authors.lastname: Jacquemont
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marlin
authors.forename: Marleen
authors.initials: M
authors.lastname: Simon
authors.forename: John
authors.initials: J
authors.lastname: Tolmie
authors.forename: Alain
authors.initials: A
authors.lastname: Verloes
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Valérie
authors.initials: V
authors.lastname: Cormier-Daire
mesh_terms: D003062:Codon; D003456:Cryptorchidism / Q000235:genetics*; D019066:Facies; D005347:Fibroblasts / Q000378:metabolism; 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*; D009154:Mutation; D010766:Phosphorylation; D051901:Smad4 Protein / Q000235:genetics*; D054875:Ubiquitination
chemical_list: D003062:Codon; D051901:Smad4 Protein