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

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...

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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
Online Access	Get full text
ISSN	0002-9297 1537-6605 1537-6605
DOI	10.1016/j.ajhg.2011.12.011

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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.
AbstractList	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 beta 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. 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. 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. [PUBLICATION 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.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. 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.
Author	Silengo, Margherita Bocchinfuso, Gianfranco Dentici, Maria Lisa Melis, Daniela Tartaglia, Marco Stella, Lorenzo Caputo, Viviana Belligni, Elga Carrani, Eugenio Garavelli, Livia Niceta, Marcello Ciolfi, Andrea Biamino, Elisa Andria, Generoso Gelb, Bruce D. Boccone, Loredana Carta, Claudio Dallapiccola, Bruno Cianetti, Luciano
AuthorAffiliation	1 Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome 00161, Italy 3 Servizio Informatico, Documentazione, Biblioteca e Attività Editoriali, Istituto Superiore di Sanità, Rome 00161, Italy 7 Genetica Clinica e Malattie Rare, II Clinica Pediatrica, Ospedale Microcitemico, Cagliari 09121, Italy 6 Genetica Clinica, Dipartimento di Ostetrico-Ginecologico e Pediatrico, Istituto di Ricerca e Cura a Carattere Scientifico Arcispedale Santa Maria Nuova, Reggio Emilia 42123, Italy 2 Dipartimento di Scienze e Tecnologie Chimiche, Università di Roma “Tor Vergata,” Rome 00133, Italy 10 Neuromed, IRCCS, Pozzilli (IS) 86077, Italy 5 Dipartimento di Scienze Pediatriche, Università di Torino, Turin 10126, Italy 9 Child Health and Development Institute, Mount Sinai School of Medicine, New York, NY 10029, USA 8 Dipartimento di Pediatria, Facoltà di Medicina e Chirurgia, Università “Federico II,” Naples 80131, Italy 4 Ospedale Bambino Gesù, Rome 00165, Italy
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Copyright	2012 The American Society of Human Genetics 2015 INIST-CNRS Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved. Copyright Cell Press Jan 13, 2012 2012 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved. 2012 The American Society of Human Genetics
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Snippet	Myhre syndrome is a developmental disorder characterized by reduced growth, generalized muscular hypertrophy, facial dysmorphism, deafness, cognitive deficits,...
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SubjectTerms	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
Title	A Restricted Spectrum of Mutations in the SMAD4 Tumor-Suppressor Gene Underlies Myhre Syndrome
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